EP3846854A2

EP3846854A2 - Improved polypeptide coupled antibiotics

Info

Publication number: EP3846854A2
Application number: EP19769720.4A
Authority: EP
Inventors: Walter Mier; Florian UMSTÄTTER; Philipp UHL; Cornelius DOMHAN
Original assignee: Individual
Current assignee: Universitaet Heidelberg
Priority date: 2018-09-04
Filing date: 2019-09-04
Publication date: 2021-07-14
Also published as: WO2020049015A2; WO2020049015A3

Abstract

The present invention relates to antibiotics comprising at least one polypeptide of a length of 2 to 20 amino acids, wherein the N-terminus of the polypeptide is not attached to a lipophilic group and the polypeptide is positively charged.

Description

IMPROVED POLYPEPTIDE COUPLED ANTIBIOTICS

The present invention relates to an antibiotic comprising at least one polypeptide, wherein the N-termlniis of the polypeptide is not attached to a lipophilic group and preferably the polypeptide is positively charged and comprises optionally a linker connecting the antibiotic and the polypeptide as well as the use of such antibiotics for the treatment of bacterial infections.

BACKGROUND OF THE INVENTION

Gram-positive bacteria cause more than 1,000,000 infections and 18,000 deaths per year in the United States, compared to 50,000 infections resulting in 3,200 deaths caused by Gram- negative bacteria [1] However, the most threatening problem is the appearance of multiresistant bacteria [2] The World Health Organization (WHO) published in 2017 a list of twelve families of bacteria that pose the greatest threat to human health. The intention of this list is to seive as a guideline for research and development of new antibiotics. The WHO emphasizes new antibiotics against vancomycin resistant Enterococci as a high priority topic [3]

The glycopeptide antibiotic vancomycin is long known and was first approved in 1958 and the molecule structure was determined first in 1982 [4]. Vancomycin is the pivotal antibiotic for treatment of multi-drug resistant infections, caused by Gram-positive bacteria [5] and is on the WHO list of Essential Medicines [6] Due to the high prevalence of infections caused by methicillin-resistant Staphylococcus aureus (MRSA), the use of vancomycin has dramatically increased in past years.

Vancomycin prevents the stabilization of the bacterial cell wall by inhibiting the cross- linking of peptidoglycan, which is an essential component of the cell wall of Gram-positive bacteria. The mechanism of action involves binding to lipid II, which is the precursor of peptidoglycan.

Nevertheless, vancomycin has non-optimal pharmacokinetic properties, which requires 2 to 3 intravenous doses per day. Furthermore, vancomycin has a variable tissue penetration, is slowly bactericidal and shows nephro- and ototoxicity [5].

Several vancomycin resistant bacterial strains are known, with vancomycin resistant Enterococci (VRE) being of the most clinical importance. For bacteremia caused by VRE a mortality rate of 25% was observed [8]. The intrinsic resistance of Enterococci against penicillins, cephalosporins, clindamycin and aminoglycosides [9] and their ability to acquire foreign resistance genes through plasmids or transposons [10] is problematic.

Vancomycin resistant Enterococci were first reported in 1988 [11] and several types of resistance genes and mechanisms_· ranging from VanA to VanG, are described [5] The most potent resistance mechanism is VanA, which is also transferable to other species. In 2002, a vancomycin resistant Staphylococcus aureus (VRSA), containing a VanA gene was isolated [12]. Similarly, a transferable VanB resistance gene was found in Streptococcus bovis [13].

The target of vancomycin is the terminal amino acid sequence D-Ala-D-Ala of the peptidoglycan precursor Lipid II muropeptide [7] The mechanism of VanA and VanB resistance is the replacement of D-Aia-D-Ala by D-Ala-D-Lac, while VanC resistance results in D-Ala-D- Ser. Furthermore, this change in sequence results in a repulsive interaction, which leads to a 1,000 fold lower affinity of vancomycin to Lipid P [14]. For the treatment of vancomycin resistant Enterococci , the ribosome targeting drugs linezolid and tigecycline are currently available [5] However, linezolid resistant Enterococci have become more common and have emerged as a serious problem throughout the last years [15].

Another limiting factor for the use of possible alternatives is the risk of heteroresistances, i.e. the carry-over of additional resistance genes. The use of lipoglycopeptides is therefore not approved, despite their activity against VanB isolates, due to the risk that in addition to VanB a VanA gene could be carried from the isolate [16].

Another drawback of the lipoglycopeptides oritavancin and dalbavancin is their extremely long plasma half-life bearing the risk of exposure to sub therapeutic drug levels [17], which enhances the selection of resistant bacteria [18] Furthermore, the new lipoglycopeptides lack activity against isolates containing VanA resistance. These factors limit the use lipoglycopeptides against vancomycin resistant Enterococci. Currently, no bactericidal therapy against VanA Enterococci is approved.

These examples demonstrate the paramount importance and urgent need for novel therapeutics in this area. Nevertheless, the number of new antibiotics appearing on the market is low. Therefore, the modification of common antibiotics such as vancomycin in order to overcome common resistance mechanisms is of high interest.

LIST OF FIGURES

In the following, the content of the figures comprised in this specification is described. In this context, please also refer to the detailed description of the invention above and/or below.

Figure 1: Membrane staining sites. 1A) the bright field image after 30 min of treatment with vancomycin at 5x MIC, IB) the fluorescence image of a 30 min vancomycin treatment where living cells are indicated by the membrane-impermeable DAPI (blue), while dead cells are indicated by the membrane-impermeable PI (red), 2A) the bright field image of a 30 min treatment with a dye-labeled vancomycin-conjugate at 5x MIC of the uniabeled conjugate, 2B) the fluorescent image of the dye-labeled conjugate (green) (arrow shows the accumulation of the conjugate in the hotspot of cell division and cell wall synthesis), 2C) the PI image of the conjugate showing dead cells, 2D) the overlay of image 2B and 2C which shows that the DNA-binding dye PI is Inside the bacterial cells, while the conjugate targets the boundary of the cell.

Figure 2: Biodistribution studies of preferred conjugates a) Biodistribution of a vancomycin- conjugate consisting of a peptide with the sequence yRRRRRRC (SEQ ID NO: 10) coupled with a linker (SMCC) on the vancomycin- V^-position (corresponding to X₃ of structure (I)) (tested in a single mouse), b) Biodistribution of a vancomycin-conjugate consisting of a peptide with the sequence Myristic acid-RRRyC (SEQ ID NO: 13) coupled with a linker (SMCC) on the vancomycin-V_N-position (tested in a single mouse), c) Biodistribution of a vancomycin-conjugate consisting of a peptide with the sequence yRRRRRRC (SEQ ID NO: 10) coupled with a linker (SMPEGg) on the vancomycin-V_N-position (tested in a single mouse), d) Biodistribution of a vancomycin- conjugate consisting of a peptide with the sequence yRRRRRRRRRC (SEQ ID NO: 16) coupled with a linker (SMCC) on the vancomycin-V_N-position (tested in three mice).

Figure 3: Scintigraphy of preferred conjugates a) Scintigraphic image of a vancomycin-conjugate consisting of a peptide with the sequence yRRRRRRC (SEQ ID NO: 10) coupled with a linker (SMCC) on the vancomycin-V_N-position after 10 min, 30 min, 60 min and 120 min. b) Scintigraphic image of a vancomycin-conjugate consisting of a peptide with the sequence Myristic acid-RRRyC (SEQ ID NO: 13) coupled with a linker (SMCC) on the vancomycin-V_N-position after 10 min, 30 min, 60 min and 120 min c) Scintigraphic image of a vancomycin-conjugate consisting of a peptide with the sequence yRRRRRRC (SEQ ID NO: 10) coupled with a linker (SMPEGg) on the vancomycin- V_N-position after 10 min, 30 min, 60 min and 120 min d) Scintigraphic image of a vancomycin-conjugate consisting of a peptide with the sequence yRRRRRRRRRC (SEQ ID NO: 16) coupled with a linker (SMCC) on the vancomycin-V_N-position after 10 min 30 min 60 min and 120 min

Figure 4: Preferred conjugation sites of vancomycin A) Preferred conjugation site of vancomycin

(V_v) modified with ethylene diamine, B) preferred conjugation site of vancomycin (V_N) and C) basic backbone structure for glycopeptide antibiotics and possible modification sites. Figure 5: Animal trials with a sepsis (MRS A systemic infection) model a) Colony foiming units of Staphylococcus aureus USA 300 in the liver of infected mice after 4 days of treatment with either 0.9% NaCl-solution as negative control, vancomycin as positive control and a vancomycin-conjugate consisting of a peptide with the sequence RRRRRRC (SEQ ID NO: 10) coupled with a linker (SMCC) on the vancomycin-V_N-position (FU002). b) Weight of the infected mice during the treatment c) Weight loss of the infected mice during the treatment period.

Figure 6: MIC of preferred modification on different strains. Left graph refers to the MIC in pg/ml of a vancomycin-conjugate consisting of a peptide with the sequence RRRRRRC (SEQ ID NO: 10) coupled with a linker (SMCC) on the vancomycin-V_N-position (FU002) tested on different strains of Enterococci. Right graph refers to the MIC in mol/ml of a vancomycin-conjugate consisting of a peptide with the sequence RRRRRRC (SEQ ID NO: 10) coupled with a linker (SMCC) on the vancomycin- V_N-position (FU002) tested on Enterococcus faecium UL602570. The level of resistance indicated in the graphs, sometimes also referred to as a breakpoint, refers to a concentration of an antibiotic which defines whether a species of bacteria is susceptible or resistant to the antibiotic. If the MIC is less than or equal to the level of resistance the bacteria is considered susceptible to the antibiotic. If the MIC is greater than this value the bacteria is considered intermediate or resistant to the antibiotic.

Figure 7: MIC values of tested conjugation sites of vancomycin. Different variation possibilities of vancomycin describing the l inking position, the used linking method (with ethylene diamine or without) and the coupled peptide. R6: Peptide of six arginine residues; R9: Peptide of nine arginines; Myr: myristyl group; V_c corresponds to Cc, V_R corresponds to X₄, V_N corresponds to X₃, V_v corresponds to X_2.

Figure 8: Structure of FU002. Vancomycin-conjugate consisting of a peptide with the sequence

RRRRRRC (SEQ ID NO: 10) coupled with a linker (SMCC) on the vancomycin-V_N- position.

Figure 9: Comparison of the minimal inhibitory concentration (MIC) and the minimal bactericidal concentration (MBD) of a vancomycin-conjugate consisting of a peptide with the sequence. RRRRRRRRRC (SEQ ID NO: 16) coupled with a linker (SMCC) on the vancomycin- V^-position.

Figure 10: Cytotoxic effect of a vancomycin-conjugate consisting of a peptide with the sequence

RRRRRRC (SEQ ID NO: 10) coupled with a linker (SMCC) on the vancomycin- V_N- position on Peripheral Blood Mononuclear cells.

Figure 11 : Structure of a vancomycin derivative with a lipophilic group attached to the N-terminus of a polypeptide, referred to as vancapticin 15. Vancapticin 15 is an example of a vancomycin derivative as known from Blaskovich et al. (Nature communications, 2018, 9:22)

Figure 12: Direct comparison of FU002 (see fig. 8) with Vancapticin 15 (see fig. 11). FU002 is significantly more active against VanA resistant Enterococcus faecium UL 602570

(n>5).

Figure 13: Direct comparison of Vancomycin-Vc-R3 with Vancomycin-Vc-R3 -Caproic acid. Vc- R3 is significantly more active against VanA resistant Enterococcus faecium UL 602570.

Figure 14: Comparison of vancomycin with two different vancomycin conjugates containing either the peptide sequence of KKKKKKC (SEQ ID NO: 47) or RRRKKKC (SEQ ID NO: 48) on three different bacterial strains of Enterococci. No values for vancomycin-Vn- R3K3 on ATCC51299 and ATCC700327 are shown.

Figure 15: Comparison of vancomycin with three different vancomycin conjugates consisting of a peptide with the sequence RRRRRRRRRC (SEQ ID NO: 16) coupled with a linker (SMCC) on the vancomycin- V_fj-position (R9-conjugate), Vancapticin 14 (Blaskovich et al., Nature communications, 2018, 9:22; Table 1, Id 14) and Vancapticin 15 (see figure 11 and Blaskovich et al., Nature communications, 2018, 9:22; Table 1, Id 15).

Figure 16: Deglycosylation of FU002 ensures the X₃-position of the conjugated peptide. Analytic was performed by HPLC-MS. Figure 17: Effect on cell viability of the vancomycin conjugate FU002 (see figure 8) and vancomycin. Liver cells used were HepG2 cells and kidney cells are HEK-293 cells.

Figure 18: Biodistribution studies of ¹²⁵I-radiolabeled FU002y and vancomycin in Wistar rats.

Tissue distribution was determined 10 min (A) and 1 h (B) post application (n=3, error bars indicate SD). FU002y predominantly accumulates in the liver.

Figure 19: Blood-level of ¹²⁵I-radiolabelled FU002y in comparison to vancomycin. No significant difference in the blood concentration between vancomycin and FU002 was detected.

Figure 20: PET-imaging of i.v. injected ¹²⁴I-radiolabelled FU002 shows after 10 minutes an accumulation in the liver in contrast to vancomycin, which is rapidly excreted by the kidneys. Insertion of longer PEG chains between vancomycin and the peptide moiety (PEG-FU002; PEG₂₄ chain) again dirigates to the kidneys.

Figure 21: Minimal inhibitory concentrations of further vancomycin conjugates in direct comparison to vancomycin (Vanco) are depicted. The level of resistance of the particular strain is indicated in the graphs as dotted line.

Figure 22: The structures of the vancomycin conjugates of figure 21 are depicted. (A) FU037, (B)

FU040, (C) FU042, (D) FU043, (E) FU044 and (F) FU045.

Figure 23: Overview of further vancomycin conjugates that have been synthesized. The MIC of these conjugates has been tested on E. faecium UL602570.

Figure 24: Structure of the teicopianin conjugate FU003.

Figure 25: MIC testing of FU003 (teicoplanin-conjugate) in comparison with teicopianin. FU003 shows improved (i.e. lower) MIC values and breaks the level of resistance.

Figure 26: Structure of the daptomycin-conjugate FU004.

Figure 27: Scintigraphic images and biodistribution of FU004 at different time points (t = 10 min.

1 h, 2 h and 3 h). Figure 28: Scintigraphic images and biodistribution of daptomycin at different time points (t = 10 min, 1 h and 3 h).

Figure 29: An in vivo toxicity study in SWISS (CD-I) mice according to the standard dosing scheme of vancomycin was performed. Vancomycin and saline were used as controls. (A) Body weight development was not affected by treatment with the vancomycin conjugate FU002. (B) Four different blood parameters were assessed. Treatment with FU002 (upright triangle) did not adversely affect albumin levels (ALB), ala.niue- aminotransferase (ALT), alkaline phosphatase (ALP) or amylase (AMY). No toxic effects with respect to FU002 could be observed.

Figure 30: Vancomycin conjugate FU007, wherein the polypeptide is comprised in atachment ot position X4 (VR). The MIC value of FU007 for E.faecium UL602570 are 22,5625 pg/ml (i.e. 8.13978x1 O ⁰⁹ mol/ml). Measurement of MIC values was performed twice in duplicate in a concentration of 3.61 mg/ml.

SUMMARY OF THE INVENTION

In a first aspect, the present invention relates to an antibiotic comprising at least one polypeptide P_p of a length of 2 to 20 amino acids, preferably of a length of 2 to 12 amino acids, wherein the N-terminus of the polypeptide is not attached to a lipophilic group and the polypeptide preferably is positively charged and optionally a linker connecting the antibiotic and the polypeptide is comprised in the antibiotic.

In a second aspect, the present invention relates to an antibiotic of one of the structures (I) or (II)

wherein:

P_p is a polypeptide of a length of 2 to 40, preferably 2 to 20, amino acids;

L is a linker;

X_j is selected from: -OH, -(NH)_r-(CH₂)_s-N-(CH₂)₂, -P_P and -L-P_P,

wherein r is selected from 0 or 1, s is an integer ranging from 1 to 6, preferably 2 to 4, more preferably 3 to 4,

with the proviso that the N-temiinus of P_p is preferably not attached to a lipophilic group;

X₂ is selected from

wherein Yi is selected from -H, -OH, and -NH-Y_¾

wherein Y₉ is selected from -H, -(CH₂)_V-NH₂, -CCH₂)_V-NH-(CH₂)_W-CH₃,(4- halobiphenyl), -P_p or -3 -P_P, wherein v is an integer ranging from 1 to 4, w is an integer ranging from 6 to 12, P_p is said polypeptide and L is said linker,

wherein Y₂ is selected from -H and -C¾,

wherein Y₆ is selected from -H, and -0-Y₈,

wherein Y₈ is a substituted tetrahydrofiiranyl, preferably a substituted tetrahydrofuranyl- 3-4-diol, more preferably 2-(hydroxymethyl)tetrahydroftiranyl-3-3-diol, wherein Y₃ is (i) a branched or unbranched C₈ to C₁₂ alkyl or alkenyl, preferably a C₉ alkenyl or a C_n alkyl; or

(ii) a branched or unbranched C₃ to Ci₉ alkyl or alkenyl, preferably a branched or unbranched C₅ to Cn alkyl or alkenyl, more preferably a C₅ to C_l7 alkyl, most preferably a C₉ to C_n alkyl.

X₃ is selected from— NX₁₄-CH₃ and -NH-X₁₅,

wherein X₁₄ is selected from -H, -P_p and -L-P_p,

wherein X₁₅ is selected from -H, -P_p and -L-P_p;

X₄ is selected from -H, -(CH₂)_n-NH -(0¾-R_R -(CH₂)_n-NH-(CH₂)_tf-L-P_P; -(CH₂)_n-NH-P_P, - (CH₂)_n-NH-L-P_P -P_p, -L-P_p and a substituted phosphonic acid, preferably substituted methylamino-phosphonic acid, wherein n is an integer ranging from 1 to 4, preferably 2 to 3, wherein n’ is an integer ranging from 1 to 4, preferably 2 to 3;

X₅ is selected from -H, and substituted tetrahydropyranyl, preferably amino-methyl-hydroxy- tetrahydropyranyl or (dihydroxy-hydroxymethyl-tetrahydropyran)-acetamide;

Xe is selected from -H, -Cl, -F, -Br, and -I;

X₇ is selected from -H, -Cl, -F, -Br, and -I;

X₈ is selected from -H and -O-Y₁₀,

wherein Y₁₀ is selected from -H and substituted tetrahydropyranyl, preferably hydroxymethyl-trihydroxy-tetrahydropyranyl;

X₉ is selected from -H or substituted tetrahydropyranyl, preferably hydroxymethyl— trihydroxy- tetrahydropyranyl or (methylacetate)-trihydroxytetrahydro-pyranyl;

Xio is selected from acetamide and substituted or unsubstituted phenyl, preferably phenyl or halobenzyl, and

Xu is selected from C₃ to C₆ alkyl, preferably a C₄ alkyl, preferably 2-methyl-proply, substituted phenyl, preferably methyl-trihydroxy-tetrahydropyranyl substituted phenyl;

or

Xio and Xu are linked by substituted or unsubstituted diphenyl ether, preferably a substituted or unsubstituted hydroxyphenoxy-phenyl, more preferably hydroxyphenoxy-phenyl, halo- hydroxyphenoxy-phenyl or methyl-hydroxyphenoxy-phenyl;

X₁₂ is selected from -CH₂-QH, -COOH, and -0-Y_u,

wherein Yu is substituted tetrahydropyranyl, preferably methyltrihydioxytetrahydropyranyl, wherein the antibiotic of (I) comprises at least one P_P;

or

wherein W) is selected from -P_p and -L-P_p.

In a third aspect of the present invention the antibiotic of the first or second aspect is for use in the treatment or prophylaxis of a bacterial infection.

In a fourth aspect of the present invention the antibiotic of the first or second aspect is for use as a medicament. DETAILED DESCRIPTION OF THE INVENTION

Before the present invention is described in detail below, it is to be understood that this invention is not limited to the particular methodology, protocols and reagents described herein as these may vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to limit the scope of the present invention which will be limited only by the appended claims. Unless defined otherwise, all technical and scientific terms used herein have the same meanings as commonly understood by one of ordinary skill in the art.

Preferably, the terms used herein are defined as described in "A multilingual glossary of biotechnological terms: (IUPAC Recommendations)" , Leuenberger, H.G.W, Nagel, B. and Kolbl, H. eds. (1995), Helvetica Chimica Acta, CH-4010 Basel, Switzerland).

Throughout this specification and the claims, which follow, unless the context requires otherwise, the word "comprise", and variations such as "comprises" and "comprising", will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps. In the following passages,

to different aspects of the invention are defined in more detail. Each aspect so defined may be combined with any other aspect or aspects unless clearly indicated to the contrary. In particular, any feature indicated as being optional, preferred or advantageous may be combined with any other feature or features indicated as being optional, preferred or advantageous.

Several documents are cited throughout the text of this specification. Each of the documents cited herein (including all patents, patent applications, scientific publications, manufacturer's specifications, instructions etc.), whether supra or infra, is hereby incorporated by reference in its entirety. Nothing herein is to be construed as an admission that the invention is not entitled to antedate such disclosure by virtue of prior invention. Some of the documents cited herein are characterized as being“incorporated by reference In the event of a conflict between the definitions or teachings of such incorporated references and definitions or teachings recited in the present specification, the text of the present specification takes precedence.

In the following, the elements of the present invention will be described. These elements are listed with specific embodiments; however, it should be understood that they may be combined in any manner and in any number to create additional embodiments. The variously described examples and preferred embodiments should not be construed to limit the present invention to only the explicitly described embodiments. This description should be understood to support and encompass embodiments which combine the explicitly described embodiments with any number of the disclosed and/or preferred elements. Furthermore, any permutations and combinations of all described elements in this application should be considered disclosed by the description of the present application unless the context indicates otherwise.

Definitions

In the following, some definitions of terms frequently used in this specification are provided. These terms will, in each instance of its use, in the remainder of the specification have the respectively defined meaning and preferred meanings.

As used in this specification and the appended claims, the singular forms "a", "an", and "the" include plural referents, unless the content clearly dictates otherwise.

In the following definitions of the terms: alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaiyl, heteroaralkyl, alkenyl, heterocycloalkenyl and alkynyl are provided. These terms will in each instance of its use in the remainder of the specification have the respectively defined meaning and preferred meanings.

The term“alkyl” refers to a saturated straight or branched carbon chain. Preferably, the chain comprises from 1 to 10 carbon atoms, i.e. 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 e.g. methyl, ethyl methyl, ethyl, propyl. so-propyl, butyl, so-butyl, ferf-butyl, pentyl, hexyl, pentyl, or octyl. Alkyl groups are optionally substituted.

The term“heteroalkyl” refers to a saturated straight or branched carbon chain. Preferably, the chain comprises from 1 to 9 carbon atoms, i.e. 1, 2, 3, 4, , 6, 7, 8, 9 e.g. methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, .sec-butyl, ferf-butyl, pentyl, hexyl, pentyl, octyl, which is interrupted one or more times, e.g. 1, 2, 3, 4, 5, with the same or different heteroatoms. Preferably the heteroatoms are selected from O, S, and N, e.g. -0-C¾, -S-C¾, -CH₂-0-CH₃, -CH₂-0-C₂H₅, - CH₂-S-C¾, -CH₂-S-C₂H_s, -C₂H₄-0-C¾, -C₂H₄-0-C₂H₅, -C₂H4-S-CH₃, -C₂H₄-S-C₂H₅ etc. Heteroalkyl groups are optionally substituted.

The terms "cycloalkyl" and "heterocycloalkyl", by themselves or in combination with other terms, represent, unless otherwise stated, cyclic versions of "alkyl" and "heteroalkyl", respectively, with preferably 3, 4, 5, 6, 7, 8, 9 or 10 atoms forming a ring, e.g. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl etc. The terms "cycloalkyl" and "heterocycloalkyl" are also meant to include bicyclic, tricyclic and polycyclic versions thereof. The term“heterocycloalkyl” preferably refers to a saturated ring having five of which at least one member is a N, O or S atom and which optionally contains one additional O or one additional N; a saturated ring having six members of which at least one member is a N, O or S atom and which optionally contains one additional O or one additional N or two additional N atoms; or a saturated bicyclic ring having nine or ten members of which at least one member is a N, O or S atom and which optionally contains one, two or three additional N atoms. “Cycloalkyl” and “heterocycloalkyl” groups are optionally substituted. Additionally, for heterocycloalkyl, a heteroatom can occupy the position at which the heterocycle is attached to the remainder of the molecule. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1- cyclohexenyl, 3-cyclohexenyl, cycloheptyl, spiro[3,3]heptyl, spiro[3,4]octyl, spiro[4,3]octyl, spiro[3,5]nonyl, spiro[5,3]nonyl, spiro[3,6]decyl, spiro[6,3]decyl, spiro[4,5]decyl, spiro[5,4]decyl, bicyclo[2.2. ljheptyl, bicyclo[2.2.2]octyl, adamantyl, and the like. Examples of heterocycloalkyl include 1 -(1 ,2,5 ,6-tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3-morpholinyl, 1,8 diazo-spiro-[4,5] decyl, 1,7 diazo-spiro-[4,5] decyl, 1,6 diazo- spiro-[4,5] decyl, 2,8 diazo-spiro[4,5] decyl, 2,7 diazo-spiro[4,5] decyl, 2,6 diazo-spiro[4,5] decyl, 1,8 diazo-spiro-[5,4] decyl, 1,7 diazo-spiro-[5,4] decyl, 2,8 diazo-spiro-[5,4] decyl, 2,7 diazo- spiro[5,4] decyl, 3,8 diazo-spiro[5,4] decyl, 3,7 diazo-spiro[5,4] decyl, l-azo-7,l l-dioxo- spiro[5,5] undecyl, 1 ,4-diazabicyclo[2.2.2]oct-2-yl, tetrahydrofuran-2-yl, tetrahydrofuran-3 -yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl, 1-piperazinyl, 2-piperazinyl, and the like.

The term“aryl” preferably refers to an aromatic monocyclic ring containing 6 carbon atoms, an aromatic bicyclic ring system containing 10 carbon atoms or an aromatic tricyclic ring system containing 14 carbon atoms. Examples are phenyl, naphtyl or anthracenyl. The aryl group is optionally substituted.

The term“aralkyl” refers to an alkyl moiety, which is substituted by aryl, wherein alkyl and aryl have the meaning as outlined above. An example is the benzyl radical. Preferably, in this context the alkyl chain comprises from 1 to 8 carbon atoms, i.e. 1, 2, 3, 4, 5, 6, 7, or 8, e.g. methyl, ethyl methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, sec-butenyl, teri-butyl, pentyl, hexyl, pentyl, octyl. The aralkyl group is optionally substituted at the alkyl and/or aryl part of the group.

The term“heteroaryl” preferably refers to a five or six-membered aromatic monocyclic ring wherein at least one of the carbon atoms are replaced by 1, 2, 3, or 4 (for the five membered ring) or 1, 2, 3, 4, or 5 (for the six membered ring) of the same or different heteroatoms, preferably selected from O, N and S; an aromatic bicyclic ring system wherein 1, 2, 3, 4, 5, or 6 carbon atoms of the 8, 9, 10, 11 or 12 carbon atoms have been replaced with the same or different heteroatoms, preferably selected from O, N and S; or an aromatic tricyclic ring system wherein 1, 2, 3, 4, 5, or 6 carbon atoms of the 13, 14, 15, or 16 carbon atoms have been replaced with the same or different heteroatoms, preferably selected from O, N and S. Examples are oxazolyl, isoxazolyl, 1,2,5- oxadiazolyl, 1 ,2,3-oxadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, thiazolyl, isothiazolyl, 1 ,2,3 ,-thiadiazolyl, 1 ,2,5-thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, 1,2,3- triazinyl, 1,2,4-triazinyl, 1,3,5-tiiazinyl, 1-benzofuranyl, 2-benzofuranyl, indoyl, isoindoyl, benzothiophenyl, 2-benzothiophenyl, lH-indazolyl, benzimidazolyl, benzoxazolyl, indoxazinyl, 2, 1 -benzosoxazoyl, benzothiazolyl, 1 ,2-benzisothiazolyl, 2, 1-benzisothiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, quinolinyl, 1 ,2,3 -benzotiiazinyl, or 1,2,4- benzotriazinyl.

The term“heteroaralkyl” refers to an alkyl moiety, which is substituted by heteroaryl, wherein alkyl and heteroaryl have the meaning as outlined above. An example is the 2- alklypyridinyl, 3-alkylpyridinyl, or 2-methylpyridinyl. Preferably, in this context the alkyl chain comprises from 1 to 8 carbon atoms, i.e. 1, 2, 3, 4, 5, 6, 7, or 8, e.g. methyl, ethyl methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, sec-butenyl, ferf-butyl, pentyl, hexyl, pentyl, octyl. The heteroaralkyl group is optionally substituted at the alkyl and/or heteroaryl part of the group.

The terms“alkenyl” and“cycloalkenyl” refer to olefinic unsaturated carbon atoms containing chains or rings with one or more double bonds. Examples are propenyl and cyclohexenyl. Preferably, the alkenyl chain comprises from 2 to 8 carbon atoms, i.e. 2, 3, 4, 5, 6, 7, or 8, e.g. ethenyl, 1 -propenyl, 2-propenyl, iso-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, iso- butenyl, sec-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, hexenyl, pentenyl, octenyl. Preferably the cycloalkenyl ring comprises from 3 to 8 carbon atoms, i.e. 3, 4, 5, 6, 7, or 8, e.g. 1- cyclopropenyl, 2-cyclopropenyl, 1-cyclobutenyl, 2-cylcobutenyl, 1-cyclopentenyl, 2 cyclopentenyl, 3-cyclopentenyl, cyclohexenyl, cyclopentenyl, cyclooctenyl.

The term“heterocycloalkenyl” preferably refers to olefinic unsaturated carbon atoms containing rings with one or more double bonds. At least one member of the ring is a N, O or S atom. A ring having five members of which at least one member is a N, O or S atom and which optionally contains one additional O or one additional N. A ring having six members of which at least one member is a N, O or S atom and which optionally contains one additional O or one additional N or two additional N atoms; or a bicyclic ring having nine or ten members of which at least one member is a N, O or S atom and which optionally contains one, two or three additional N atoms.“Heterocycloalkenyl” groups are optionally substituted. Additionally, a heteroatom can occupy the position at which the heterocycle is attached to the remainder of the molecule. Examples of heterocycloalkenyl include azirine, diazirene, oxirene, thiirene, azete, diazete, oxete, dioxete, thiete, dithiete, pyrroline, furanyl, thiophenyl, imidazoline, pyrazoline, oxazoline, thiazoline, pyridine, pyran or thiopyran.The term“alkynyl” refers to unsaturated carbon atoms containing chains or rings with one or more triple bonds. An example is the propargyl radical. Preferably, the alkynyl chain comprises from 2 to 8 carbon atoms, i.e. 2, 3, 4, 5, 6, 7, or 8, e.g. ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3- pentynyl, 4-pentynyl, hexynyl, pentynyl, octynyl.

In one embodiment, carbon atoms or hydrogen atoms in alkyl, heteroalkyl, cycloalkyl, aryl, aralkyl, alkenyl, cycloalkenyl, heterocycloalkenyl, alkynyl radicals may be substituted independently from each other with one or more elements selected from the group consisting of O, S, N or with groups containing one or more elements selected from the group consisting of O, S, N.

Embodiments include alkoxy, cycloalkoxy, arykoxy, aralkoxy, alkenyloxy, cycloalkenyloxy, alkynyloxy, alkylthio, cycloalkylthio, arylthio, aralkylthio, alkenylthio, cycloalkenylthio, alkynylthio, alkylamino, cycloalky lamino, arylamino, aralkylamino, alkenylamino, cycloalkenylamino, alkynylamino radicals.

Other embodiments include hydroxyalkyl, hydroxycycloalkyl, hydroxyaryl, hydroxy aralkyl, hydroxyalkenyl, hydroxycycloalkenyl, hydroxyalinyl, mercaptoalkyl, mercaptocycloalkyk, mercaptoaryl, mercaptoaralkyl, mercaptoalkenyl, mercaptocycloalkenyl, mercaptoalkynyl, aminoalkyl, aminocycloalkyl, aminoaryl, aminoara.1ky1, aminoalkenyl, aminocycloalkenyl, aminoalkynyl radicals.

In another embodiment, hydrogen atoms in alkyl, heteroalkyl, cycloalkyl, aryl, aralkyl, alkenyl, cycloalkenyl, alkynyl radicals may be substituted independently from each other with one or more halogen atoms. One radical is the trifluoromethyl radical. If two or more radicals or two or more residues can be selected independently from each other, then the term“independently” means that the radicals or the residues may be the same or may be different.

As used herein a wording defining the limits of a range of length such as, e. g.,“from 1 to 6” means any integer from 1 to 6, i. e. 1, 2, 3, 4, 5 and 6. In other words, any range defined by two integers explicitly mentioned is meant to comprise and disclose any integer defining said limits and any integer comprised in said range.

The term“halo” as used herein refers to a halogen residue selected from the group consisting of F, Br, I and Cl. Preferably, the halogen is Cl.

The term“linker” and“L” are interchangeably used herein to refer to any chemically suitable linker. Preferably, linkers are not or only slowly cleaved under physiological conditions. Thus, it is preferred that the linker does not comprise recognition sequences for proteases or recognition structures for other degrading enzymes. Since it is preferred that the compounds of the invention are administered systemically, it is preferred that the linker is chosen in such that it is not or only slowly cleaved in blood. The cleavage is considered slowly, if less than 50% of the linkers are cleaved 2 h after administration of the compound to a human patient. Suitable linkers, for example, comprises or consists of optionally substituted alkyl, heteroalkyl, cycloalkyl, cycloheteroalkyl, aryl, heteroaryl, aralkyl, heteroaralyl, alkenyl, heteroalkenyl, cycloalkenyl, cycloheteroalkenyl, alkynyl, sulfonyl, amines, ethers, thioethers phosphines, phosphoramidates, carboxamides, esters, imidoesters, amidines, thioesters, sulfonamides, 3 -thiopyrrolidine-2 , 5 -dion, carbamates, ureas, guanidines, thioureas, disulfides, oximes, hydrazines, hydrazides, hydrazones, diaza bonds, triazoles, triazolines, tetrazines, platinum complexes and amino acids, or combinations thereof. Preferably, the linker comprises or consists of 1, 4-piperazine, 1,3 -propane and a phenolic ether or combinations thereof.

The expression“optionally substituted” refers to a group in which one, two, three or more hydrogen atoms may have been replaced independently of each other by the respective substituents.

As used herein, the term’'amino acid" refers to any organic acid containing one or more amino substituents, e.g. a-, b- or g-amino, derivatives of aliphatic carboxylic acids. In the polypeptide notation used herein, e.g. Xaa5, i.e. XaalXaa2Xaa3Xaa4Xaa5 , wherein Xaal to Xaa5 are each and independently selected from amino acids as defined, the left hand direction is the amino terminal direction and the right hand direction is the carboxy terminal direction, in accordance with standard usage and convention.

The term "conventional amino acid" refers to the twenty naturally occurring amino acids, and encompasses all stereomeric isoforms, i.e. D, L-, D- and T ,-amino acids thereof. These conventional amino acids can herein also be referred to by their conventional three- letter or one- letter abbreviations and their abbreviations follow conventional usage (see, for example, Immunology— A Synthesis, 2nd Edition, E. S. Golub and D. R. Gren, Eds., Sinauer Associates,

Sunderland Mass. (1991)).

The term "non-conventional amino acid" refers to unnatural amino acids or chemical amino acid analogues, e.g. a,a-disubstituted amino acids, N-alkyl amino acids, homo-amino acids, dehydroamino acids, aromatic amino acids (other than phenylalanine, tyrosine and tryptophan), and ortho-, meta- or para-aminobenzoic acid. Non-conventional amino acids also include compounds which have an amine and carboxyl functional group separated in a 1,3 or larger substitution pattern, such as b-alanine, g-amino butyric acid, Freidinger lactam, the bicyclic dipeptide (BTD) , amino-methyl benzoic acid and others well known in the art. Statine-like isosteres, hydroxyethylene isosteres, reduced amide bond isosteres, thioamide isosteres, urea isosteres, carbamate isosteres, thioether isosteres, vinyl isosteres and other amide bond isosteres known to the art may also be used. The use of analogues or non-conventional amino acids may improve the stability and biological half-life of the added peptide since they are more resistant to breakdown under physiological conditions. The person skilled in the art will be aware of similar types of substitution which may be made. A non-limiting list of non-conventional amino acids which may be used as suitable building blocks for a peptide and their standard abbreviations (in brackets) is as follows: a-aminobutyric acid (Abu), L-N-methylalanine (Nmala), a-amino-a- methylbutyrate (Mgabu), L-N-methylarginine (Nmarg), aminocyclopropane (Cpro), L-N- methylasparagine (Nmasn), carboxylate L-N-methylaspartic acid (Nmasp), aniinoisobutyric acid (Aib), L-N-methylcysteine (Nmcys), aminonorbomyl (Norb), L-N-methylglutamine (Nmgln), carboxylate L-N -methylglutamic acid (Nmglu), cyclohexylalanine (Chexa), L-N-methylhistidine (Nmhis), cyclopentylalanine (Cpen), L-N-methylisolleucine (Nmile), L-N-methylleucine (Nmleu), L-N-methyllysine (Nmlys), L-N-methylmethionine (Nmmet), L-N-methylnorleucine (Nrnnle), L-N-methylnorvaline (Nmnva), L-N-methylomithine (Nmom), L-N- methylphenylalanine (Nmphe), L-N-methylproline (Nmpro), L-N-methylserine (Nmser), L-N- methylthreonine (Nmthr), L-N-methyltryptophan (Nmtrp), D-omithine (Dorn), L-N- methyltyrosine (Nmtyr), L-N-methylvaline (Nmval), L-N-methylethylglycine (Nmetg), L-N- methyl-t-butylglycine (Nmtbug), L-norleucine (NIe), L-norvaline (Nva), a-methyl- aminoisobutyrate (Maib), a-methyl-y-aminobutyrate (Mgabu), D-a-methylalanine (Dmala), a- methylcyclohexylalanine (Mchexa), D-a-methylarginine (Dmarg), a-methylcylcopentylalanine (Mcpen), D-a-methylasparagine (Dmasn), a-methyl-a-napthylalanine (Manap), D-a- methylaspartate (Dmasp), a-methylpenicillamine (Mpen), D-a-methylcysteine (Dmcys), N-(4- aminobutyl)glycine (Nglu), D-a-methylglutamine (Dmgln), N-(2-aminoethyl)glycine (Naeg), D- a-methylhistidme (Dmhis), N-(3 -ammopropyl)glycine (Nom), D-a-methylisoleucine (Dmile), N- amino-a-methylbutyrate (Nmaabu), D-a-methylleucine (Dmleii), a-napthylalanine (Anap), D-a- methyllysine (Dmlys), N-benzylglycine (Nphe), D-a-methylmethionine (Dmmet), N-(2- carbamylethyl)glycine (Ngln), D-a-methylomithine (Dmom), N-(carbamylmethyl)glycine (Naso), D-a-metliylphenylalanine (Dmphe), N-(2-carboxyethyl)glycine (Nglu), D-a- methylproline (Dmpro), N-(carboxymethyl)glycine (Nasp), D-a-methylserine (Dmser), N- cyclobiitylglycine (Ncbut), D-a-methylthreonine (Dmthr), N-cycloheptylglycine (Nchep), D-a- metliyltryptophan (Dmtrp), N-cyclohexylglycine (Nchex), D-a-methyltyrosine (Dinty), N-cyclo- decylglycine (Ncdec), D-a-methylvaline (Dmval), N-cylcododecylglycine (Ncdod), D-N- metliylalanine (Dmnala), N-cyclooctylglycine (Ncoct), D-N-methyiarginine (Dnmarg), N- cyclopropylglycine (Ncpro), D-N-methylasparagine (Dmnasn), N-cycloundecylglycine (Ncund), D-N-methylaspartate (Dnmasp), N-(2,2-diphenylethyl)glycine (Nbhm), D-N-methylcysteine (Dnmcys), N-(3 ,3 -diphenylpropyl)glycine (Nbhe), D-N-methylglutamine (Dnmgln), N-(3 - guanidinopropyl)glycine (Narg), D-N-metliylglutamate (Dnmglu), N-( 1 -hydroxyethyl)glycine (Ntbx), D-N-metliylliistidine (Dnmhis), N-(hydroxyethyl))glycine (Nser), D-N-methylisoleucine (Dnmile), N-(imidazolylethyl))glycine (Nhis), D-N-methylleucine (Dmiileu), N-(3 indolylyetliyl)glycine ( itrp), D-N-methyllysine (Dnnilys), N-methyl-y-aminobutyrate (Nmgabu), N-methylcyclohexylalanine (Nmchexa), D-N-methylmethionine (Dnmmet), D-N- methyl ornithine (Dmnom), N-methylcyclopentylalanine (Nmcpen), N-methylglycine (Nala), D- N-methylphenylalanine (Dnmphe), N-methylaminoisobutyrate (Nmaib), D-N-methylproline (Dnmpro), N-( 1 -methylpropyl)glycine (Nile), D-N-methylserine (Dnmser), N-(2- methylpropyl)glycine (Nleu), D-N-methylthreonine (Dnmthr), D-N-methyltryptophan (Dmntrp), N-( 1 -methylethyl)glycine (Nval), D-N-methyltyrosine (Dnmtyr), N-methyla-napthylalanine (Nmanap), D-N-methylvaline (Dmnval), N-methylpenicillamine (Nmpen), g-aminobutyric acid (Gabu), N-(p-hydroxyphenyl)glycme (Nhtyr), L-/-butylglycine (Tbug), N-(thiomethyl)glycine (Ncys), L-ethylglycine (Etg), penicillamine (Pen), L-homophenylalanine (Hphe), L-a- methylalanine (Mala), L-a-methylarginine (Marg), L-a-methylasparagine (Masn), L-a- methylaspartate (Masp), L-a-methyl-t-butylglycine (Mtbug), L-a-methylcysteine (Mcys), L- methylethylglycine (Metg), L-a-methylglutamine (Mgln), L-a-methylglutamate (Mglu), L-a- methylhistidine (Mhis), L-a-methylhomophenylalanine (Mhplie), L-a-methylisoleucine (Mile), N-(2-methylthioethyl)glycine (Nmet), L-a-methylleucine (Mien), L-a-metliyllysine (Mlys), L-a- methylmethionine (Mmet), L-a-methylnorleucine (Mnle), L-a-methylnorvaline (Mnva), L-a- metbylomitMne (Mom), L-a-methylphenylalanine (Mphe), L-a-methylproline (Mpro), L-a- metliylserine (Mser), L-a-methylthreonine (Mthr), L-a-methyltiyptophan (Mtrp), L-a- methyltyrosine (Mtyr), L-a-methylvaline (Mval), L-N-methylhomophenylalanine (Nmhphe), N- (N-(2,2-diphenylethyl)carbamylmethyl)glycine (Nnbhm), N-(N-(3 ,3 -diphenylpropyl)- carbamylmethyl)glycine (Nnbhe), 1 -carboxy- 1 -(2,2-diphenyl-ethylamino)cyclopropane (Nmbc), L-O-metliyl serine (Omser), L-O-metliyl homoserine (Omhser).

The term“N-contaimng aromatic or non-aromatic mono or bicyclic heterocycle” as used herein refers to a cyclic saturated or unsaturated hydrocarbon compound which contains at least one nitrogen atom as constituent of the cyclic chain.

The term "pharmaceutically acceptable salt" refers to a salt of the compound of the present invention. Suitable pharmaceutically acceptable salts of the compound of the present invention include acid addition salts which may, for example, be formed by mixing a solution of choline or derivative thereof with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, sulfuric acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, citric acid, tartaric acid, carbonic acid or phosphoric acid. Furthermore, where the compound of the invention carries an acidic moiety, suitable pharmaceutically acceptable salts thereof may include alkali metal salts (e.g., sodium or potassium salts); alkaline earth metal salts (e.g., calcium or magnesium salts); and salts formed with suitable organic ligands (e.g., ammonium, quaternary ammonium and amine cations formed using counteranions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, alkyl sulfonate and aryl sulfonate). Illustrative examples of pharmaceutically acceptable salts include but are not limited to: acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, butyrate, calcium edetate, camphorate, camphorsulfonate, camsylate, carbonate, chloride, citrate, clavulanate, cyclopentanepropionate, digluconate, dihydrochloride, dodecylsulfate, edetate, edisylate, estolate, esylate, ethanesulfonate, formate, fumarate, gluceptate, glucoheptonate, gluconate, glutamate, glycerophosphate, glycolylarsanilate, hemisulfate, heptanoate, hexanoate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroiodide, 2-hydroxy-ethanesulfonate, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laurate, lauryl sulfate, malate, maleate, malonate, mandelate, mesylate, methanesulfonate, methylsulfate, mucate, 2- naphthalenesulfonate, napsylate, nicotinate, nitrate, N-methylglucamine ammonium salt, oleate, oxalate, pamoate (embonate), palmitate, pantothenate, pectinate, persulfate, 3-phenylpropionate, phosphate/diphosphate, picrate, pivalate, polygalacturonate, propionate, salicylate, stearate, sulfate, subacetate, succinate, tannate, tartrate, teoelate, tosylate, triethiodide, undecanoate, valerate, and the like (see, for example, Berge, S. M., et al, "Pharmaceutical Salts", Journal of Pharmaceutical Science, 1977, 66, 1-19). Certain specific compounds of the present invention contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts. The term“pharmaceutical composition” as used in the present application refers to a substance and/or a combination of substances being used for the identification, prevention or treatment of a tissue status or disease. The pharmaceutical composition is formulated to be suitable for administration to a patient in order to prevent and/or heat disease. Further a pharmaceutical composition refers to the combination of an active agent with a carrier, inert or active, making the composition suitable for therapeutic use. Pharmaceutical compositions can be formulated for oral, parenteral, topical, inhalative, rectal, sublingual, transdermal, subcutaneous or vaginal application routes according to their chemical and physical properties. Pharmaceutical compositions comprise solid, semisolid, liquid, transdermal therapeutic systems (TTS). Solid compositions are selected from the group consisting of tablets, coated tablets, powder, granulate, pellets, capsules, effervescent tablets or transdermal therapeutic systems. Also comprised are liquid compositions, selected from the group consisting of solutions, syrups, infusions, extracts, solutions for intravenous application, solutions for infusion or solutions of the carrier systems of the present invention. Semisolid compositions that can be used in the context of the invention comprise emulsion, suspension, creams, lotions, gels, globules, buccal tablets and suppositories.

“Pharmaceutically acceptable” means approved by a regulatory agency of the Federal or a state government or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in animals, and more particularly in humans.

The term“carrier”, as used herein, refers to a diluent, adjuvant, excipient, or vehicle with which the therapeutic agent is administered. Such pharmaceutical carriers can be sterile liquids, such as saline solutions in water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like. A saline solution is a preferred carrier when the pharmaceutical composition is administered intravenously. Saline solutions and aqueous dextrose and glycerol solutions can also be employed as liquid carriers, particularly for injectable solutions. Suitable pharmaceutical excipients include starch, glucose, lactose, sucrose, gelatine, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol and the like. The composition, if desired, can also contain minor amounts of wetting or emulsifying agents, or pH buffering agents. Examples of suitable pharmaceutical carriers are described in "Remington's Pharmaceutical Sciences" by E. W. Martin.

Embodiments

In the following different aspects of the invention are defined in more detail. Each aspect so defined may be combined with any other aspect or aspects unless clearly indicated to the contrary. In particular, any feature indicated as being preferred or advantageous may be combined with any other feature or features indicated as being preferred or advantageous.

In a first aspect the present invention relates to a, antibiotic comprising at least one polypeptide of a length of 2 to 20 amino acids, preferably of a length of 2 to 12, more preferably 3 to 10 amino acids, even more preferably 4 to 8 amino acids and most preferably 6 amino acids, wherein the N-terminus of the polypeptide is not attached to a lipophilic group and is preferably positively charged and optionally comprises a linker connecting the antibiotic and the polypeptide.

The term“lipophilic group” is used herein in its meaning known in the art of chemistry. Lipophilic refers to the ability of a chemical compound to dissolve in fats, oils, lipids and non polar solvents. This definition includes e.g. lipophilic membrane insertive elements. Preferred examples include saturated and unsaturated fatty acids, C8 to C22 fatty acids, cholesterol, derivatives of cholesterol, phospholipids, glycolipids, glycerol esters, steroids, ceramids, isoprene derivatives, adamantane, famesol, aliphatic groups, or polyaromatic compounds. Preferred lipohilic groups that may be attached to the P_P in some embodiments are myristoyl (C 14), palmitoyl (C 16) or stearoyl (C 18), more preferably myristoyl (C 14).

However, the inventors surprisingly found that the addition of a lipophilic group to the polypeptide does contrary to the present teaching in the art not enhance but decrease the activity of the antibiotic derivative. Examples for this effect of the lipophilic group can be found in figures 12 and 13.

In an alternative of the first aspect the present invention relates to an antibiotic comprising an antibiotic core and at least one polypeptide of a length of 2 to 20 amino acids, preferably of a length of 2 to 12 amino acids, wherein the N-terminus of the polypeptide is not attached to a lipophilic group and the polypeptide is positively charged and optionally a linker connecting the antibiotic core and the polypeptide, wherein the antibiotic core is selected from the group consisting of a glycopeptide antibiotic; a cyclic lipopeptide antibiotic; a b-lactam antibiotic, a cephalosporine antibiotic; and an oxazolidinone antibiotic; preferably a glycopeptide antibiotic and a cyclic lipopeptide antibiotic.

In a preferred embodiment of the first aspect of the invention or its alternative the lipophilic group is not attached to any other position of the polypeptide including, but not limited to, the C- terminus and side chains of the polypeptide.

In a preferred embodiment of the antibiotics of the first aspect of the present invention or its alternative the antibiotic core is selected from the group consisting of a glycopeptide antibiotic; a cyclic lipopeptide antibiotic; a B-lactam antibiotic, preferably a cephalosporine antibiotic; an oxazolidinone antibiotic; and an aminoglycoside antibiotic. In a more preferred embodiment of the antibiotics of the first aspect of the present invention or its alternative the antibiotic core is selected from the group consisting of a glycopeptide antibiotic; a cyclic lipopeptide antibiotic; a B-lactam antibiotic, a cephalosporine antibiotic; and an oxazolidinone antibiotic.

In a most preferred embodiment of the antibiotics of the first aspect of the invention or its alternative the antibiotic core is selected from a glycopeptide antibiotic or a cyclic lipopeptide antibiotic.

In a preferred embodiment of the antibiotics of the fust aspect of the present invention or its alternative the:

(!) glycopeptide antibiotic is selected from the group consisting of vancomycin, teicoplanin, A477, A35512, A40926, A41030, A42867, A47934, A80407, A82846, A83850, A84575, AB-65, actaplanin, actinoidin, ardacin, avoparcin, azureomycin, balhimycin, chloroorientiein, chloropolyspoiin, dalbavancin, decaplanin, N-demethylvancomycin, eremomycin, galacardin, helvecardin, izupeptin, kibdelin, LL-AM374, mannopeptin, MM45289, MM47756, MM47761, MM49721, MM47766, MM55260, MM55266, MM55270, MM56597, MM56598, OA-7653, orenticin, parvodicin, ristocetin, ristomycin, synmonicin, telavancin, UK-68597, UK-69542, and UK-7205 or antibiotic structural analogs thereof;

(ii) cyclic lipopeptide antibiotic is selected from the group consisting of daptomycin, dalbavancin, oritavancin and telavancin ;

(iii) aminoglycoside antibiotic is selected from the group consisting of amikacin, and kanamycin;

(iv) B-lactam antibiotic is selected from the group consisting of penicillin, amoxicillin, and ampicillin;

(v) cephalosprine antibiotic is selected from the group consisting of cefazolin, cefadroxil, cephalexin, cefiiroxim, cefotiam, cefaclor, cefiiroxim, loracarbef, cefixim, cefpodoxim, ceftibuten, cefotaxim, ceftriaxon, ceftazidim, cefepim ceftobiprol, ceftolozan, or ceftarolin, and

(vi) oxazolidinone antibiotic is linezolid.

In a more preferred embodiment of the antibiotics of the first aspect of the present invention or its alternative the:

(i) glycopeptide antibiotic is selected from the group consisting of vancomycin, teicoplanin, A477, A35512, A40926, A41030, A42867, A47934, A80407, A82846, A83850, A84575, AB-65, actaplanin, actinoidin, ardacin, avoparcin, azureomycin, balhimycin, chloroorientiein, chloropolysporin, dalbavancin, decaplanin, N-demethylvancomycin, eremomycin, galacardin, helvecardin, izupeptin, kibdelin. LL-AM374, mannopeptin, MM45289, MM47756, MM47761, MM49721, MM47766, MM55260, MM55266, MM55270, MM56597, MM56598, OA-7653, orenticin, parvodicin, ristocetin, ristomycin, synmonicin, telavancin, UK-68597, UK-69542, and UK-7205 or antibiotic structural analogs thereof;

(iii) b-lactam antibiotic is selected from the group consisting of penicillin, amoxicillin, and ampicillin;

(iv) cephalosprine antibiotic is selected from the group consisting of cefazolin, cefadroxil, cephalexin, cefuroxim, cefotiam, cefaclor, cefuroxim, loracarbef, ceftxim, cefpodoxim, ceftibuten, cefotaxim, ceftriaxon, ceftazidim, cefepim ceftobiprol, ceftolozan, or ceftarolin, and

(v) oxazolidinone antibiotic is linezolid.

Glycopeptide antibiotics are most preferred and in particular vancomycin and structural derivatives thereof, in particular teicoplanin, avoparcin, ristocetin, parvodicin, oritavancin, dalbavancin and telavancin.

In a preferred embodiment of the antibiotic of the first aspect of the present invention or its alternative the polypeptide or the linker forms a bond to the indicated residues of structures (I) and (II) as defined in the second aspect of the invention.

In a second aspect the present invention relates to an antibiotic of one of the structures (I) or

(II)

wherein:

P_p is a polypeptide of a length of 2 to 40, preferably 2 to 20, amino acids, more preferably 3 to 10 amino acids;

L is a linker;

X_j is selected from: -OH, -(NH)_r-(CH₂)_s-N-(CH₂)₂, -P_P and -L-P_P,

with the proviso that the N-terminus of P_p is preferably not attached to a lipophilic group;

X₂ is selected from structure (

wherein Yi is selected from -H, -OH, and -NH-Y₉,

wherein Y₉ is selected from -H, -(CH₂)_V-NH₂, -(CH₂)_V-NH-(CH₂)_W-CH₃, -(CH₂)_q- chlorobiphenyl chlorobiphenyl, -P_p and -L-P_p, wherein q is an integer ranging from 1 to 4, preferably 1 to 2, v is an integer ranging from 1 to 4, w is an integer ranging from 6 to 12, P_p is said polypeptide and L is said linker,

wherein Y₂ is selected from -H and -C¾,

wherein Y₆ is selected from -H, and -0-Y₈, wherein Y₈ is a substituted tetrahydrofuranyl, preferably substituted with one, two, three or four substituents independently selected from -OH, -CH₃, -C¾-OH, -NH-(C=0)- CH3, and -NH₂, in particular a substituted tetrahydrofuranyl-3-4-diol, more preferably 2- (hydroxymethyl)tetrahydrofuranyl-3 -3 -diol,

wherein Y₃ is (i) a branched or unbranched C₈ to C₁₂ alkyl or alkenyl, preferably a C₉ alkenyl or a C_n alkyl; or

(ii) a branched or unbranched C₃ to C₁₉ alkyl or alkenyl, preferably a branched or unbranched C₅ to C₁₇ alkyl or alkenyl, more preferably a C₅ to C₁₇ alkyl, most preferably a C₉ to C_n alkyl.

X₃ is selected from -NX₁₄-CH₃ and -NH-X₁₅,

wherein X_l4 is selected from -H, -P_P and -L-P_P,

wherein C ₅ is selected from -H, -P_P and -L-P_P;

X, is selected from -H, -(CH₂)_n-NH -(CH₂)_n-P_P, -(CH₂)_n-NH-(CH₂)_n-L-P_P; -(CH₂)_n-NH-P_P, -

(C¾)_n-NH-L-P_P -P_p, -L-P_p and a substituted phosphonic acid, preferably substituted methylamino-phosphonic acid, wherein n is an integer ranging from 1 to 4, preferably 2 to 3, wherein n’ is an integer ranging from 1 to 4, preferably 2 to 3;

X₅ is selected from -H, and substituted tetrahydropyranyl, preferably substituted with one, two, three or four substituents independently selected from -OH, -CH₃, -CH₂-OH, -NH-(C=0)- CH3, and -NH₂, in particular amino-methyl-hydroxy-tetrahydropyranyl, (dihydroxy- hydroxymethyl-tetrahydropyran)-acetamide, and N-acetylglucosamine ;

¾ is selected from -H, -Cl, -F, -Br, and -I, preferably H and Cl;

X₇ is selected from -H, -Cl, -F, -Br, and -I, preferably H and Cl;

Xs is selected from -H and -O-Y_l0,

wherein Y ₁₀ is selected from -H and substituted tetrahydropyranyl, preferably substituted with one, two, three or four substituents independently selected from -OH, -C¾, -C¾-OH, -NH- (C=0)-CH3, and -NH₂, in particular hydroxymethyl-trihydroxy-tetrahydropyranyl;

X₉ is selected from -H and substituted tetrahydropyranyl, preferably substituted with one, two, three or four substituents independently selected from -OH, -CH₃, -CH₂-OH, -NH-(C=0)- CH3, and -NH₂, in particular hydroxymethyl— trihydroxy-tetrahydropyranyl (methylacetate)- trihydroxytetrahydro-pyranyl, a-D-mannose;

X_l0 is selected from acetamide and substituted or unsubstituted phenyl, preferably substituted with one or two halogens, in particular phenyl or halobenzyl,

Xu is selected from C₃ to C₆ alkyl, preferably a C₄ alkyl, most preferably 2-methyl-propyl, substituted phenyl, preferably methyl-frihydroxy-tetrahydropyranyl substituted phenyl; or

X₁₀ and X_u are linked by a substituted or unsubstituted diphenyl ether, preferably each phenyl ring independently substituted with one or two substituents selected from -OH, and halogen, in particular hydroxyphenoxy-phenyl, more preferably hydroxyphenoxy-phenyl, fraio- hydroxyphenoxy-phenyl or methyl-hydroxyphenoxy-phenyl;

X₁₂ is selected from -CH₂-OH, -COOH, and -0-Y_U ,

wherein Y_u is substituted tetrahydropyranyl, preferably substituted with one, two, three or four substituents independently selected from -OH, -C¾, -CH₂-OH, -NH-(C=G)-CH3, and - N¾, in particular methyltrihydroxytetrahydropyranyl,

wherein the antibiotic of (I) comprises at least one P_p, more preferably 1 or 2 P_p most preferably one P_p;

or

wherein Wi is selected from -P_p and -L-P_p.

In an alternative of the second aspect the present invention relates to an antibiotic of one of the structures (I) or (II)

wherein:

P_p is a polypeptide of a length of 2 to 40, preferably of 2 to 20, amino acids;

L is a linker;

X_j is selected from: -OH, -(NH)_r-(CH₂)_s-N-(CH₂)₂, -(NH)-(CH₂)_U-(NH)-P_p, -(NH)-(CH₂)_U-

(NH)-L-Pp, -P_P or -L-Pp, -(C=0)-(CH₂)_t-CH₃

wherein u is an integer ranging from 1 to 4, preferably 2 to 3, r is selected from 0 or 1, s is an integer ranging from 1 to 6, preferably 2 to 4, more preferably 3 to 4, t is an integer ranging from 2 to 18, preferably 4 to 16,

with the proviso that the N-terminus of P_p is not attached to a lipophilic group;

X₂ is selected from structure (

wherein Y_t is selected from -H, -OH, and -NH-Y₉,

wherein Y₉ is selected from -H, -(CH₂)_¥-NH₂, -(CH₂)_V-NH-(CH₂)_W-CH₃, -(C=0)- (CH₂)_t-CH₃, -(CH₂)_q-chlorobiphenyl, chlorobiphenyl -(CH₂)_n-(NH)-Pp, -(CH₂)_U- (NH)-L-Pp, -P_p and -L-P_p, wherein q is an integer ranging from 1 to 4, preferably 1 to 2, u is an integer ranging from 1 to 4, preferably 2 to 3, v is an integer ranging from 1 to 4, w is an integer ranging from 6 to 12, t is an integer ranging from 2 to 18, preferably 4 to 16, P_p is said polypeptide and L is said linker,

wherein Y₂ is selected from -H and -C¾,

wherein Y₆ is selected from -H, and -0-Y₈,

wherein Y₈ is a substituted tetrahydrofuranyl, preferably a substituted tetrahydrofiiranyl-3-4-diol, more preferably 2-(hydroxymethyl)tetrahydrofuranyl-3-3- diol,

wherein Y₃ is (i) a branched or unbranched C₈ to C₁₂ alkyl or alkenyl, preferably a C₉

alkenyl or a C_n alkyl; or

(ii) a branched or unbranched C₃ to C₁₉ alkyl or alkenyl, preferably a branched or unbranched C₅ to C_l7 alkyl or alkenyl, more preferably a C₅ to C₁₇ alkyl, most preferably a C₉ to Cn alkyl.

X₃ is selected from -NX_l4-CH₃ and -NH-X₁₅,

wherein X₁₄ is selected from -H, -P_p and -L-P_p, -(CH₂)_U-(NH)-Pp, -(CH₂)_U-(NH)-L-P_p, -(C=0)-(CH₂)_t-CH₃, wherein t is an integer ranging from 4 to 16, u is an integer ranging from 1 to 4, preferably 2 to 3,

wherein X_l5 is selected from -H, -P_p and -L-P_p, -(CH₂)_U-(NH)-P_p, -(CH₂)_U-(NH)-L-P_p, -(C=0)-(CH₂)_t-CH₃ wherein t is an integer ranging from 2 to 18, preferably 4 to 16, u is an integer ranging from 1 to 4, preferably 2 to 3;

X, is selected from -H, -(CH₂)_n- H -(CH^-Pp, -(CH₂)_n-NH-(CH₂)^-L-P_P; -(CH₂)_n-NH- P_P, -(CH₂)_n-NH-L-P_P -Pp, -L-P_P and a substituted phosphonic acid, preferably substituted methylamino-phosphonic acid, wherein n is an integer ranging from 1 to 4, preferably 2 to 3, wherein n’ is an integer ranging from 1 to 4, preferably 2 to 3;

X₅ is selected from -H, or substituted tetrahydropyranyl, preferably amino-methyl- hydroxy-tetrahydropyranyl or (dihydroxy-hydroxymethyl-tetrahydropyran)-acetamide ; Xg is selected fr om -H, -Cl, -F, -Br, and -I;

X₇ is selected from -H, -Cl, -F, -Br, and -I;

X_g is selected from -H and -O-Y ₁₀,

wherein Y₁₀ is selected from -H or substituted tetrahydropyranyl, preferably hydroxymethyl-trihydroxy-tetrahydropyranyl;

X₉ is selected from -H and substituted tetrahydropyranyl, preferably hydroxymethyl— frihydiOxy-tetrahydropyranyi or (methylacetate)-trihydroxytetrahydro-pyranyl; X₁₀ is selected from acetamide and substituted or unsubstituted phenyl, preferably phenyl or halobenzyl, and X_n is selected from C₃ to C₆ alkyl, preferably a C₄ alkyl, substituted phenyl, preferably methyl-trihydroxy-tetrahydropyranyl substituted phenyl; or

X₁₀ and X_n are linked by a unsubstituted or substituted diphenyl ether, preferably a substituted or unsubstituted hydroxyphenoxy-phenyl, more preferably hydroxyphenoxy-phenyl, halo-hydroxyphenoxy-phenyl or methyl-hydroxyphenoxy- phenyl;

X₁₂ is selected from -C¾-OH, -COOH, -0-Y_U ,

wherein Y_n is substituted tetrahydropyranyl, preferably methyltiihydioxytefrahydiopyranyl,

wherein the antibiotic of (I) comprises at least one P_P;

or

wherein selected from -P_p or -L-P_p.

Structure (I) represents the backbone of at least the following glycopeptides and lipoglycopeptides: vancomycin, teicoplanin, avoparcin, ristocetin, parvodicin, oritavancin, dalbavancin and telavancin.

Elements Xi to X₄ comprise the atachment points of P_P or the linker to which the P_P is bound, if present, to the antibiotic according to structure (I). As previously outlined it is preferred that the antibiotic according to structure (I) comprises one or two, preferably one P_p or L-P_p. Accordingly, in the following preferred embodiments are indicated in which P_p or L-P_p are attached to either X_t, X₂, X₃ or X₄

Element Xy

Element X_t is part of a carboxyl group located at this position in the unmodified antibiotics. However, this position can not only be modified by the P_p, but also by other structures as indicated herein to increase the antimicrobial activity of the antibiotic.

However, in a preferred embodiment, X_x is selected from -P_p or -L-P_p;

In another preferred embodiment, X_x is selected from -(NH)-(CH₂)_U-(NH)-P_p, -(NH)- (CH₂)_U-(NH)-L-Pp, wherein u is an integer ranging from 1 to 4, preferably 2 to 3. Even more preferred Xi is selected from -(NH)-(CH₂)_U-(NH)-L-P_P, wherein u is an integer ranging from 1 to 4, preferably 2 to 3.

X₂ is selected from structure (PI), and -NH-CO-Y₃,

wherein Yi is selected from -H, -OH, and -NH-Y₉,

wherein Y₉ is selected from -H, -(CH₂)_¥-NH₂, -(CH₂)_V-NH-(CH₂)_W-CH3, -(C=0)-(CH₂)_t- CH₃, -(CH₂)_q-chlorobiphenyl, chlorobiphenyl, wherein q is an integer ranging from 1 to 4, preferably 1 to 2, t is an integer ranging from 4 to 16, wherein v is an integer ranging from 1 to 4, w is an integer ranging from 6 to 12, Y₉ is preferably selected from H, wherein Y₂ is selected from -H and -C¾,

wherein Y₆ is selected from -H, and -0-Y₈,

wherein Y₈ is a substituted tefrahydrofiiranyl, preferably substituted with one, two, three or four substituents independently selected fro -OH, -C¾, -CH₂-OH, -NH-(C=0)-CH₃, and -NH₂, in particular a substituted tetrahydrofuranyl-3 -4-diol, more preferably 2- (hydroxymethyl)tetrahydrofuranyl-3-3-diol,

wherein Y₃ is (i) a branched or unbranched C₈ to C₁₂ alkyl, i.e. C₈, C₉, C_l0, C_u or C₁₂ alkyl; or C₈ to C_l2 alkenyl, , i.e. C₈, C₉, C₁₀, C_n or C₁₂ alkenyl, preferably a C₉ alkyl, C₉ alkenyl or a C_n alkyl; non-3-en-yl (as in Teicoplanin A₂-l), 7-methyl-octanyl (as in Teicoplanin A -2), nonyl (as in Teicoplanin A₂-3), 7-methyl-nonyl (as in Teicoplanin A₂-4), or 8-methyl-nonyl

(as in Teicoplanin A₂-5); or (ii) a branched or unbranched C₃ to C₁₉ alkyl or alkenyl, preferably a branched or unbranched C₅ to C₁₇ alkyl or alkenyl, more preferably a C₅ to C₁₇ alkyl, most preferably a C₉ to Cn alkyl.

X₃ is selected from -NX₁₄-CH₃ and -NH-X₁₅,

wherein X_x4 is selected from -H, -(C=0)-(CH₂)_t-CH₃, wherein t is an integer ranging from 4 to 16; wherein X₁₅ is selected from -H, -(C=0)-(CH₂)_rCH₃, wherein t is an integer ranging from 4 to 16;

X4 is selected from -H, and a substituted phosphonic acid, preferably substituted methylamino- phosphonic acid;

X₅ is selected from -H, and substituted tetrahydropyranyl, preferably substituted with one, two, three or four substituents independently selected from -OH, -CH₃, -CH₂-OH, -NH-(C=0)- CH₃, and -NH₂, in particular amino-methyl-hydroxy-tetrahydropyranyl, (dihydroxy- hydroxymethyl-tetrahydropyran)-acetamide, and N-acetylglucosamine;

Xe is selected from -H, -Cl, -F, -Br, and -I, preferably H and Cl;

X₇ is selected from -H, -Cl, -F, -Br, and -I, preferably H and Cl;

X₈ is selected from -H and -O-Y₁₀,

wherein Y 10 is selected from -H and substituted tetrahydropyranyl, preferably substituted with one, two, three or four substituents independently selected from -OH, -C¾, -CH₂-OH, -NH- (C=0)-CH₃, and -NH₂, in particular hydroxymethyl-trihydroxy-tetrahydropyranyl;

X₉ is selected from -H and substituted tetrahydropyranyl, preferably substituted with one, two, three or four substituents independently selected from -OH, -CH₃, -CH₂-OH, -NH-(C=0)- CH , and -NH₂, in particular hydroxymethyl— trihydroxy-tetrahydropyranyl, (methylacetate)- trihydroxytetrahydro-pyranyl, a-D-mannose;

X₁₀ is selected from acetamide and substituted or unsubstituted phenyl, preferably substituted with one or two halogens, in particular phenyl or halobenzyl,

X_3l is selected from C₃ to C₆ alkyl, preferably a C₄ alkyl, most preferably 2-methyl-propyl, substituted phenyl, preferably methyl-trihydroxy-tetrahydropyranyl substituted phenyl; or

X10 and Xu are linked by a substituted or unsubstituted diphenyl ether, preferably each phenyl ring independently substituted with one or two substituents selected from -OH, and halogen, in particular hydroxyphenoxy-phenyl, more preferably hydroxyphenoxy-phenyl, halo- hydroxyphenoxy-phenyl or methyl-hydroxyphenoxy-phenyl;

X₁₂ is selected from -CH₂-OH, -COOH, and -0-Y_u,

wherein Yu is substituted tetrahydropyranyl, preferably substituted with one, two, three or four substituents independently selected from -OH, -C¾, -CH₂-OH, -NH-(C=0)-CH3 , and - NH₂, in particular methyltrihydroxytetrahydropyranyl.

In a preferred embodiment X₂ is selected from structure (III), and -NH-CO-Y_3. The variable Y 1 is selected from -H, -OH, -NH-Y9, wherein Y₉ is selected from -(CH₂)_V-NH₂, - (CH₂VNH-(CH₂)_W-CH₃, -(CH₂)_q-chlorobiphenyl and chlorobiphenyl. The index v is an integer ranging from 1 to 4, q is an integer ranging from 1 to 4, preferably 1 to 2 and the index w is an integer ranging from 6 to 12. The variable Y₂ is -H or -CH₃ The variable Y₆ is selected from -H, -0-Y₈, wherein Y₈ is a substituted tetrahydrofuranyl, preferably a substituted tetrahydrofuranyl- 3-4-diol, more preferably 2-(hydroxymethyl)tetrahydrofuranyl-3-3-diol. The variable Y₃ is (i) a branched or unbranched C₈ to C_i2 alkyl or alkenyl, preferably a C₉ alkenyl or a C_n alkyl; or (ii) a branched or unbranched C₃ to C₁₉ alkyl or alkenyl, preferably a branched or unbranched C₅ to C _j7 alkyl or alkenyl, more preferably a C₅ to C₁₇ alkyl, most preferably a C₉ to C_n alkyl.

In a preferred embodiment X₂ is selected from structure (III) and the variable Y _j is selected from NH-Y₉, wherein Y₉ is selected from H and variable Y₂ is CH_3.

In a preferred embodiment X₂ is -NH-CO-Y_3. The variable Y₃ is (i) a branched or unbranched C₈ to C₁₂ alkyl or alkenyl, preferably a C₉ alkenyl or a C_u alkyl, more preferably non-3-en-yl (as in Teicoplanin A₂-l), 7 -methyl-octanyl (as in Teicoplanin A₂-2), nonyl (as in Teicoplanin A₂-3), 7-methyl-nonyl (as in Teicoplanin A₂-4), or 8-methyl-nonyl (as in

Teicoplanin A₂-5); or (ii) a branched or unbranched C₃ to C_l9 alkyl or alkenyl, preferably a branched or unbranched C₅ to C_l7 alkyl or alkenyl, more preferably a C₅ to C_l7 alkyl, most preferably a C₉ to C_n alkyl.

In a more preferred embodiment X₂ is structure (III). The variable Y_j is selected from -H, -OH, and -NH-Y₉, wherein Y₉ is selected from -(CH₂)_V-NH₂, -(CH₂)_¥-NH-(CH₂)_W-CH₃, -(CH₂)_q- chlorobiphenyl and chlorobiphenyl. The index v is an integer ranging from 1 to 4, q is an integer ranging from 1 to 4, preferably 1 to 2 and the index w is an integer ranging from 6 to 12. The variable Y₂ is -H or -CH₃ The variable Y₆ is selected from -H, -0-Y₈, wherein Y₈ is a substituted tetrahydrofuranyl, preferably a substituted tetrahydrofuranyl-3 -4-diol, more preferably 2- (hydroxymethyl)tetrahydrofuranyl-3-3-diol.

In a most preferred embodiment the variable Yi of structure (III) is selected from -H, -OH,

_. The variable Y₂ of structure (ITT) is -H or -CH_3. The variable Y₃ of the structure of element X₂ is (i) a branched or unbranched C₈ to C₁₂ alkyl or alkenyl, preferably a C₉ alkenyl or a C_u alkyl; or (ii) a branched or unbranched C₃ to C_j9 alkyl or alkenyl, preferably a branched or unbranched C₅ to C₁₇ alkyl or alkenyl, more preferably a C₅ to C₁₇ alkyl, most preferably a C₉ to C_u alkyl. The variable Y₆ of structure (ITT) is

selected from -H or

In a most preferred embodiment the variable Uc of structure (ITT) is selected from -H, -OH,

The variable Y of the structure of element X₂ is -H or -C¾.

In a most preferred embodiment, the variable Y₃ of element X₂ is (i) a branched or unbranched C₈ to Ci₂ alkyl or alkenyl, preferably a C₉ alkenyl or a Cn alkyl; or (ii) a branched or unbranched C₃ to C_l9 alkyl or alkenyl, preferably a branched or unbranched C₅ to Ci₇ alkyl or alkenyl, more preferably a C₅ to C_l7 alkyl, most preferably a C₉ to C_u alkyl.

In a most preferred embodiment, the variable Y₆ of structure (TIT) is selected from -H or

In a preferred embodiment X4 is selected from -H, and a substituted phosphonic acid, preferably substituted methylamino phosphonic acid.

If PP is attached at position Xi it is preferred that P_P is linked through its N-terminus to the carbonyl group forming a peptide bond. If -L-P_P is attached at position XI P_P may be linked through its N- or C-terminus to L.

If P_p is attached at position X_j it is preferred that it is present under the proviso that the N- terminus of P_p is not attached to a lipophilic group.

If P_p comprises Arg, in particular comprises or consists of 3 to 9 consecutive Arg than a lipophilic group may be attached to the N-terminus.

In a preferred embodiment the lipophilic group is not attached to any other position of the polypeptide including, but not limited to, the C-terminus and side chains of the polypeptide.

Element X₇:

Element X₂ is located on the mannose derived structure indicated in structure (I). In a preferred embodiment in which -P_p or -L-P_p is part of X₂, X₂ has structure (PI), Y c is -NH-Yg, wherein Y₉ is selected from -(CH₂)_U-{NH)-P_p, -(CH₂)„-(NH)-L-P_p, -P_p and -L-Pp. wherein u is an integer ranging from 1 to 4, preferably 2 to 3. The variable Y₂ is -H or -C¾ The variable Y₆ is selected from -H, and -0-Y₈, wherein Y₈ is a substituted tetrahydrofuranyl, preferably a substituted tetrahydrofuranyl-3-4-diol, more preferably 2- (hydroxymethyl)tetrahydrofuranyl-3-3-diol.

Xx is selected from: -OH, -(C=0)-(CH₂)_t-C¾ and -(NH)_r-(CH₂)_s-N-(CH₂)₂,

wherein r is selected from 0 or 1, s is an integer ranging from 1 to 6, preferably 2 to 4, more preferably 3 to 4, t is an integer ranging from 2 to 18, preferably 4 to 16;

X₃ is selected from -NX₁₄-CH₃ and -NH-X_l5,

wherein X₁₄ is selected from -H, -(C=0)-(CH₂)_rCH₃ , wherein t is an integer ranging from 4 to 16,

wherein Cc₅ is selected from -H, -(C=0)-(CH₂)_t-CH₃ , wherein t is an integer ranging from 4 to 16;

X₄ is selected from -H, and a substituted phosphonic acid, preferably substituted methylamino- phosphonic acid;

X₅ is selected from -H, and substituted tetrahydropyranyl, preferably substituted with one, two, three or four substituents independently selected from -OH, -CH₃, -CH₂-OH, -NH-(C=0)- CH3, and -NH₂, in particular amino-methyl-hydroxy-tetrahydropyranyl, (dihydroxy- hydroxymethyl-tetrahydropyran)-acetamide, and N-acetylglucosamine;

Xg is selected from -H, -Cl, -F, -Br, and -I, preferably H and Cl;

X₇ is selected from -H, -Cl, -F, -Br, and -I, preferably H and Cl;

X_s is selected from -H and -O-Y_l0,

wherein Y c₀ is selected from -H and substituted tetrahydropyranyl, preferably substituted with one, two, three or four substituents independently selected from -OH, -CH₃, -C¾-OH, -NH- (C=0)-CH₃, and -NH₂, in particular hydroxymethyl-trihydroxy-tetrahydropyranyl;

X₉ is selected from -H and substituted tetrahydropyranyl, preferably substituted with one, two, three or four substituents independently selected from -OH, -CH₃, -CH₂-OH, -NH-(C=0)- CH₃, and -NH₂, in particular hydroxymethyl— tdhydroxy-tetrahydropyranyl (methylacetate)- trihydroxytetrahydro-pyranyl, a-D-mannose;

Xu is selected from C₃ to C₆ alkyl, preferably a C₄ alkyl, most preferably 2-methyl-propyl, substituted phenyl, preferably methyl-trihydroxy-tetrahydropyranyl substituted phenyl; or X₁₀ and X_u are linked by a substituted or unsubstituted diphenyl ether, preferably each phenyl ring independently substituted with one or two substituents selected from -OH, and halogen, in particular hydroxyphenoxy-phenyl, more preferably hydroxyphenoxy-phenyl, fraio- hydroxyphenoxy-phenyl or methyl-hydroxyphenoxy-phenyl;

X_l2 is selected from -CH₂-OH, -COOH, and -0-Y_u,

wherein Y_n is substituted tetrahydropyranyl, preferably substituted with one, two, three or four substituents independently selected from -OH, -C¾, -CH₂-OH, -NH-(C=0)-CH3 , and -NH₂, in particular methylfrihydroxytetrahydropyranyl.In a preferred embodiment X_j is selected from - OH, and -(NH)_r-(CH₂)_s-N-(CH₂)_2. The index r is selected from 0 or 1 , with 0 signifying the absence of the indicated element. Index s is an integer ranging from 1 to 6, preferably 2 to 4, more preferably 3 to 4, most preferably 4. The modification -(CH₂)₄-N-(CH₂)₂ refers to a modification disclosed in Yarlagadda et al. (J Med Chem. 2014 Jun 12;57(11):4558-68).

In a preferred embodiment X₄ is selected from -H, and a substituted phosphonic acid, preferably substituted methylamino phosphonic acid.

In a preferred embodiment, the N-terminus of the polypeptide P_p comprised in element X₂ is not attached to a lipophilic group.

In a preferred embodiment, the lipophilic group is not attached to any other position of the polypeptide P_p comprised in element X₂ including, but not limited to, the C -terminus and side chains of the polypeptide.

Element X₃:

Element X₃ is located at the position of a methyl amine group in the unmodified antibiotic. In the embodiment in which the P_P or -L-P_P is comprised in X₃ one of X_l4 and X_l5 is selected from -(CH₂)_U-(NH)-P_p, -(CH₂)_n-(NH)-L-Pp, -P_P or -L-P_P and the other is -H, wherein u is an integer ranging from 1 to 4, preferably 2 to 3;

X_! is selected from: -OH, -(C=0)-(CH₂)_t-CH₃ and -(NH)_r-(CH₂)_s-N-(CH₂)₂,

X₂ is selected from structure (PI), and -NH-CO-Y₃,

wherein Y_x is selected from-H, -OH, and -NH-Y₉,

wherein Y₉ is selected from -H, -(C¾)_¥-NH₂, -(€H₂)_n-NH-(€H₂ ,-€H₃, -(C=0)-(CH₂)_t- CH₃, -(CH₂)_q-chlorobiphenyl, chlorobiphenyl, wherein v is an integer ranging from 1 to 4, w is an integer ranging from 6 to 12, q is an integer ranging from 1 to 4, preferably 1 to 2, and t is an integer ranging from 2 to 18, preferably 4 to 16,

wherein Y₂ is selected from -H and -C¾, wherein Y₆ is selected from -H, and -0-Y₈,

wherein Y₈ is a substituted tetrahydrofuranyl, preferably substituted with one, two, three or four substituents independently selected from -OH, -CH₃, -CH₂-OH, -NH-(C=0)- CH3, and -NH₂, in particular a substituted tetrahydrofiiranyl-3-4-diol, more preferably 2- (hydroxymethyl)tetrahydrofuranyl-3 -3 -diol,

wherein Y₃ is (i) a branched or unbranched C₈ to C_l2 alkyl or alkenyl, preferably a C₉ alkenyl or a C_u alkyl; or

Xg is selected from -H, -Cl, -F, -Br, and -I, preferably H and Cl;

X₇ is selected from -H, -Cl, -F, -Br, and -I, preferably H and Cl;

X₈ is selected from -H and -O-Y₁₀,

X_u is selected from C₃ to C₆ alkyl, preferably a C₄ alkyl, most preferably 2-methyl-propyl, substituted phenyl, preferably methyl-trihydroxy-tetrahydropyranyl substituted phenyl; or

Xio and X_u are hnked by a substituted or unsubstituted diphenyl ether, preferably each phenyl ring independently substituted with one or two substituents selected from -OH, and halogen, in particular hydroxyphenoxy-phenyl, more preferably hydroxyphenoxy-phenyl, halo- hydroxyphenoxy-phenyl or methyl-hydroxyphenoxy-phenyl; X₁₂ is selected from -CH₂-OH, -COOH, and -0-Y_u,

wherein Yu is substituted tetrahydropyranyl, preferably substituted with one, two, three or four substituents independently selected fr om -OH, -C¾, -CH₂-OH, -NH-(C=0)-CH3 , and - N¾, in particular methyltrihydroxytefrahydropyranyl.

In a preferred embodiment X_t is selected from -OH, and -(NH)_r-(CH₂)_s-N-(CH₂)2_· The index r is selected from 0 or 1, with 0 signifying the absence of the indicated element. Index s is an integer ranging from 1 to 6, preferably 2 to 4, more preferably 3 to 4, most preferably 4.

In a preferred embodiment X is selected from structure (III), and -NH-CO-Y_3. The variable Y_j is selected from -H, -OH, -NH-Y₉, wherein Y₉ is selected from -(CH₂)_V-NH₂, - (CH₂)_V-NH-(CH₂)_W-CH₃, -(C=0)-(CH₂)_rCH₃, -(CH₂)_q-chlorobiphenyl and chlorobiphenyl. The index q is an integer ranging from 1 to 4, preferably 1 to 2, v is an integer ranging from 1 to 4, t is an integer ranging from 4 to 16 and the index w is an integer ranging from 6 to 12'. The variable Y₂ is -H or -CH₃ The variable Y₆ is selected from -H, -0-Y₈, wherein Y₈ is a

substituted tetrahydrofuranyl, preferably a substituted tetrahydrofuranyl-3 -4-diol, more preferably 2-(hydroxymethyl)tetrahydrofuranyl-3-3-diol. The variable Y₃ is (i) a branched or unbranched C₈ to C₁₂ alkyl or alkenyl, preferably a C₉ alkenyl or a C_u alkyl; or (ii) a branched or unbranched C₃ to C_l9 alkyl or alkenyl, preferably a branched or unbranched C₅ to C₁₇ alkyl or alkenyl, more preferably a C₅ to C₁₇ alkyl, most preferably a C₉ to C_u alkyl.

In a preferred embodiment X₂ is -NH-CO-Y_3. The variable Y₃ is (i) a branched or unbranched C₈ to C_l2 alkyl or alkenyl, preferably a C₉ alkenyl or a Cu alkyl, more preferably non-3-en-yl (as in Teicoplanin A₂-l), 7 -methyl-octanyl (as in Teicoplanin A₂-2), nonyl (as in Teicoplanin A₂-3), 7-methyl-nonyl (as in Teicoplanin A₂-4), or 8-methyl-nonyl (as in

Teicoplanin A₂-5); or (ii) a branched or unbranched C₃ to C₁₉ alkyl or alkenyl, preferably a branched or unbranched C₅ to C₁₇ alkyl or alkenyl, more preferably a C₅ to C₁₇ alkyl, most preferably a C₉ to C_n alkyl.

In a more preferred embodiment X₂ is structure (PI). The variable Y_j is selected from -H, -OH, and -NH-Y₉, wherein Y₉ is selected from -(CH₂)_V-NH₂, -(CH₂)_¥-NH-(CH₂)_W-CH₃, -(CH₂)_q- chlorobiphenyl and chlorobiphenyl. The index v is an integer ranging from 1 to 4, q is an integer ranging from 1 to 4, preferably 1 to 2, and the index w is an integer ranging from 6 to 12. The variable Y₂ is -H or -C¾ The variable Y₆ is selected from -H, -0-Y₈, wherein Y₈ is a substituted tetrahydrofuranyl, preferably a substituted tetrahydrofuranyl-3 -4-diol, more preferably 2- (hydroxymethyl)tetrahydrofiiranyl-3-3-diol. In a most preferred embodiment the variable Y₃ of structure (ITT) is selected from -H, -OH,

_. The variable Y₂ of structure (ITT) is -H or -CH₃. The variable Y₃ of the structure of element X₂ is (i) a branched or imbranched C₈ to C₁₂ alkyl or alkenyl, preferably a C₉ alkenyl or a C_u alkyl; or (ii) a branched or unbranched C₃ to

C_j9 alkyl or alkenyl, preferably a branched or imbranched C₅ to C₁₇ alkyl or alkenyl, more preferably a C₅ to C₁₇ alkyl, most preferably a C₉ to C_u alkyl. The variable Y₆ of structure (PI) is

selected from -H or

In a most preferred embodiment the variable Y₃ of structure (III) is selected from -H, -OH,

The variable Y₂ of the structure of element X₂ is -H or -CH .

In a most preferred embodiment, the variable Y₃ of element X₂ is (i) a branched or unbranched C₈ to C₁₂ alkyl or alkenyl, preferably a C₉ alkenyl or a Cu alkyl; or (ii) a branched or imbranched C₃ to C₁₉ alkyl or alkenyl, preferably a branched or unbranched C₅ to C₁₇ alkyl or alkenyl, more preferably a C₅ to C_l7 alkyl, most preferably a C₉ to Cu alkyl.

In a most preferred embodiment, the variable Y₆ of structure (III) is selected from -H or

In a preferred embodiment X₄ is selected from -H, and a substituted phosphonic acid, preferably substituted methylamino phosphonic acid. In a more preferred embodiment, X₄ is selected from

IfX₃ is P_p, Pp may be attached through its N- or C -terminus.

In a preferred embodiment, the N-terminus of the polypeptide P_p comprised in element X₃ is not attached to a lipophilic group.

In a preferred embodiment, the lipophilic group is not attached to any other position of the polypeptide P_P comprised in element X₃ including, but not limited to, the C -terminus and side chains of the polypeptide.

Element X₄:

Element X₄ is located on an aromatic ring structure of the antibiotic.

In the preferred embodiment in which P_p, -L-P_p is comprised in X₄, X₄ is selected from - (CH₂)_n-NH -(CH₂)_tf-P_P -(C¾)_I1-NH-(CH₂)_n ^,-L-P_P; -(C¾)_n-NH-P_P, -(CH₂)_n-NH-L-P_P -P_p, and - L-P_p, wherein n is an integer ranging from 1 to 4, preferably 2 to 3, wherein n is an integer ranging from 1 to 4, preferably 2 to 3, optionally n and/or n’ can be 0.

Xi is selected from: -OH, -(C=0)-(CH₂),-CH₃ and -(NH)_r-(CH₂)_s-N-(CH₂)₂,

X₂ is selected from structure (III), and -NH-CO-Y₃,

wherein Yi is selected from -H, -OH, and -NH-Y₉,

wherein Y₉ is selected from -H, -(CH₂)_V-NH₂, -(€H₂)_n-NH-(€H₂ qH₃, -(C=0)-(CH₂)_t- CH₃, -(CH₂)_q-chlorobiphenyl, chlorobiphenyl, wherein t is an integer ranging from 4 to 16, wherein q is an integer ranging from 1 to 4, preferably 1 to 2, v is an integer ranging from 1 to 4, i.e. 1, 2, 3, or 4, preferably 2, w is an integer ranging from 6 to 12, i.e. 6, 7, 8, 9, 10, 11, or 12;

wherein Y₂ is selected from -H and -CH₃,

wherein Y₆ is selected from -H, and -0-Y₈,

wherein Y₈ is a substituted tetrahydrofuranyl, preferably substituted with one, two, three or four substituents independently selected from -OH, -CH₃, -C¾-OH, -NH-(C=0)- CH3, and -NH₂, in particular a substituted tetrahydrofiiranyl-3-4-diol, more preferably 2- (hydroxymethyl)tetrahydrofuranyl-3 -3 -diol,

wherein Y₃ is (i) a branched or unbranched C₈ to C₁₂ alkyl or alkenyl, preferably a C₉ alkenyl or a C_u alkyl; or (ii) a branched or unbranched C₃ to C₁₉ alkyl or alkenyl, preferably a branched or unbranched C₅ to C₁₇ alkyl or alkenyl, more preferably a C₅ to C₁₇ alkyl, most preferably a C₉ to Cn alkyl;

X₃ is selected from -NX_I4-CH₃ and -NH-Xu,

wherein X₁₄ is selected from -H, -(C=0)-(CH₂)_t-CH₃, wherein t is an integer ranging from 4 to 16;

wherein X₁₅ is selected from -H, -(C=0)-(CH₂)_t-CH₃, wherein t is an integer ranging from 4 to 16;

¾ is selected from -H, -Cl, -F, -Br, and -I, preferably H and Cl;

X₇ is selected from -H, -Cl, -F, -Br, and -I, preferably H and Cl;

X_s is selected from -H and -O-Y₁₀,

Xio is selected from acetamide and substituted or unsubstituted phenyl, preferably substituted with one or two halogens, in particular phenyl or halobenzyl,

X_n is selected from C₃ to C₆ alkyl, preferably a C₄ alkyl, most preferably 2-methyl-propyl, substituted phenyl, preferably methyl-trihydroxy-tetrahydropyranyl substituted phenyl; or

X₁₀ and Xu are linked by a substituted or unsubstituted diphenyl ether, preferably each phenyl ring independently substituted with one or two substituents selected from -OH, and halogen, in particular hydroxyphenoxy-phenyl, more preferably hydroxyphenoxy-phenyl, haio- hydroxyphenoxy-plienyl or methyl-hydroxyphenoxy-phenyl;

X₁₂ is selected from -C¾-OH, -COOH, and -0-Y_u,

wherein Yu is substituted tetrahydropyranyl, preferably substituted with one, two, three or four substituents independently selected from -OH, -C¾, -CH₂-OH, -NH-(C=0)-CH3 , and - NH₂, in particular· methyltrihydroxytetrahydropyranyl. In a preferred embodiment X_t is selected from -OH, and -(NH)_r-(CH₂)_s-N-(CH₂)2. The index r is selected from 0 or 1, with 0 signifying the absence of the indicated element. Index s is an integer ranging from 1 to 6, preferably 2 to 4, more preferably 3 to 4, most preferably 4.

In a preferred embodiment X₂ is selected from structure (III), and -NH-CO-Y3. The variable Y 1 is selected from -H, -OH, -NH-Y_¾ wherein Y₉ is selected from -(CH₂)_V-NH₂, -(CH₂)_V- NH-(CH₂)_W-CH₃, -(CH₂)_q-chlorobiphenyl and chlorobiphenyl. The index q is an integer ranging from 1 to 4, preferably 1 to 2, v is an integer ranging from 1 to 4 and the index w is an integer ranging from 6 to 12'. The variable Y₂ is -H or -C¾ The variable Y₆ is selected from -H, -0-Y₈, wherein Y₈ is a substituted tetrahydrofuranyl, preferably a substituted tetrahydrofuranyl-3-4-diol, more preferably 2-(hydroxymethyl)tetrahydrofuranyl-3 -3 -diol. The variable Y₃ is (i) a branched or unbranched C₈ to C₁₂ alkyl or alkenyl, preferably a C₉ alkenyl or a C_u alkyl; or (ii) a branched or unbranched C₃ to C19 alkyl or alkenyl, preferably a branched or unbranched C₅ to C17 alkyl or alkenyl, more preferably a C₅ to C17 alkyl, most preferably a C₉ to C alkyl.

In a preferred embodiment X₂ is selected from structure (III) and the variable Y 1 is selected from NH-Y₉, wherein Y₉ is selected from H and variable Y₂ is CH₃.

In a preferred embodiment X₂ is -NH-CO-Y₃. The variable Y₃ is (i) a branched or unbranched C₈ to C₁₂ alkyl or alkenyl, preferably a C₉ alkenyl or a C_u alkyl, more preferably 11011- 3-en-yl (as in Teicoplanin A₂-l), 7-methyl-octanyl (as in Teicoplanin A₂-2), nonyl (as in Teicoplanin A₂-3), 7-methyl-nonyl (as in Teicoplanin A₂-4), or 8-methyl-nonyl (as in Teicoplanin A -5); or (ii) a branched or unbranched C₃ to C₁₉ alkyl or alkenyl, preferably a branched or imbranched C₅ to C_l7 alkyl or alkenyl, more preferably a C₅ to C₁₇ alkyl, most preferably a C₉ to Cu alkyl.

In a more preferred embodiment X₂ is structure (PI). The variable Y 1 is selected from -H, -OH, and -NH-Y₉, wherein Y₉ is selected from -(CH₂)_V-NH₂, -(CH₂)_¥-NH-(CH₂)_W-CH₃, -(CH₂)_q- chlorobiphenyl and chlorobiphenyl. The index q is an integer ranging from 1 to 4, preferably 1 to 2, v is an integer ranging from 1 to 4 and the index w is an integer ranging from 6 to 12. The variable Y₂ is -H or -CH₃ The variable Y₆ is selected from -H, -0-Y₈, wherein Y₈ is a substituted tetrahydrofuranyl, preferably a substituted tetrahydrofuranyl-3 -4-diol, more preferably 2- (hydroxymethyl)tetrahydrofuranyl-3-3-diol.

In a most preferred embodiment the variable Y ₁ of structure (III) is selected from -H, -OH, ₂ (III) is -H or -CH_3. The variable Y₃ of the structure of element X₂ is (i) a branched or unbranched C₈ to Ci₂ alkyl or alkenyl, preferably a C₉ alkenyl or a C_n alkyl; or (ii) a branched or unbranched C₃ to C₁₉ alkyl or alkenyl, preferably a branched or unbranched C₅ to C₁₇ alkyl or alkenyl, more preferably a C₅ to C₁₇ alkyl, most preferably a C₉ to Cn alkyl. The variable Y₆ of structure (III) is selected from -H and

In a most preferred embodiment the variable Uc of structure (III) is selected from -H, -OH,

, The variable Y₂ of the structure of element X₂ is -H or -C¾.

In a most preferred embodiment, the variable Y₃ of element X₂ is (i) a branched or unbranched C₈ to C₁₂ alkyl or alkenyl, preferably a C₉ alkenyl or a Cn alkyl; or (ii) a branched or unbranched C₃ to C₁₉ alkyl or alkenyl, preferably a branched or unbranched C₅ to C₁₇ alkyl or alkenyl, more preferably a C₅ to C₁₇ alkyl, most preferably a C₉ to C_n alkyl.

In a most preferred embodiment, the variable Y₆ of structure (III) is selected from -H and

If X4 is or comprises P_p, P_p may be attached through its N- or C -terminus.

In a preferred embodiment, the N-terminus of the polypeptide P_p comprised in element X₄ is not attached to a lipophilic group. In a preferred embodiment, the lipophilic group is not attached to any other position of the polypeptide P_p comprised in element X4 including, but not limited to, the C -terminus and side chains of the polypeptide. Elements X_s to Xyj.

The elements X₅ to X₁₂ provide modifications to the backbone structure of the antibiotic according to structure (I) have the below preferred and particularly preferred meanings. In particular in each of the preferred above outlined cases in which X_l3 X₂, X₃ or X₄ is or comprises -P_p or -L-Pp X₅ to _j2 have the following preferred meanings.

In a preferred embodiment X₅ is selected from -H, or substituted tetrahydropyranyl, preferably amino-methyl-hydroxy-tetrahydropyranyl or (dihydroxy-hydroxymethyl- tetrahydropyran)-acetamide.

In a more preferred embodiment, X₅ is selected from

(dihydroxy-hydroxymethyl-tetrahydropyran)-acetamide) and

In a preferred embodiment X₆ is selected from -H or a halogen, preferably -Cl.

In a preferred embodiment X₇ is selected from -H or a halogen, preferably -Cl.

In a preferred embodiment X₈ is selected from -H or -O-Y _10. The variable Y₁₀ is selected from -H or a substituted tetrahydropyranyl, preferably hydroxymethyl— trihydroxy- tetrahydropyranyl . In a more preferred embodiment, X₈ is selected from -OH, -H, and

In a preferred embodiment X₉ is selected from -H or a substituted tetrahydropyranyl, preferably hydroxymethyl— trihydroxy-tetrahydropyranyl or (methylacetate)- trihydroxytetrahydro-pyranyl.

In a more preferred embodiment, X₉ is selected from -H and

wherein Y₇ is selected from -H or -CO-CH_3.

In a preferred embodiment X₁₀ is selected from a acetamide or substituted or unsubstituted phenyl, preferably phenyl or halobenzyl.

In a more preferred embodiment, X₁₀ is selected from and

, wherein Y₅ is selected from -H or -Cl.

In a preferred embodiment X_n is selected from C₃ to C₆ alkyl, preferably a C₄ alkyl, substituted phenyl, preferably methyl-trihydroxy-tetrahydropyranyl substituted phenyl. In a more preferred embodiment, X_n is selected from C₃ to C₆ alkyl, preferably a C₄ alkyl,

In an alternative preferred embodiment, the elements X₁₀ and Xu are linked by an element. X_l0 and u are linked by substituted phenyl ether, preferably a substituted or unsubstituted hydroxyphenoxy-phenyl, more preferably hydroxyphenoxy-phenyl, halo-hydroxyphenoxy- phenyl or methyl-hydroxyphenoxy-phenyl.

In a more preferred alternative embodiment, X₁₀ and X_u are linked by

, whereby Y₄ is selected from -H, -CH , or -Cl. In a preferred embodiment X₁₂ is selected from -CH₂-OH, -COOH, -0-Y_n The variable

Yu is substituted tetrahydropyranyl, preferably methyltrihydroxytetrahydropyranyl.

In a more preferred embodiment, X₁₂ is selected from -CH₂-OH, -COOH or

It is particularly preferred that in the various substituents of the antibiotic according to structure (I) the substituents g to X₁₂ take on their respective meaning in vancomycin and structural derivatives thereof, in particular teicoplanin, avoparcin, ristocetin, parvodicin, oritavancin, dalbavancin and telavancin, wherein one or two, preferably one of X_l or X₄ is or comprises -P_p or -L-P_p or X₂ or X₃ comprises -P_p or -L-P_p.

Thus, preferably for an antibiotic comprising -P_p or -L-P_p attached to vancomycin one of X_l or X₄ is or comprises -P_p or -L-P_p or one of X₂ or X₃ comprises -P_p or -L-P_p, X_j is OH, X₂ is structure (PI) and Yi is -NH₂, Y₂ is CH₃ and Y₆ is -H, X₃ is -NH-CH₃, X₄ to X₇ is H, X₈ is -OH, X₉ is -H, X₁₀ is -(C=0)-NH₂, Xu is-2-mehtyl-propyl, and C ₂ is -CH₂-OH.

Thus, preferably for an antibiotic comprising -P_p or -L-P_p attached to teicoplanin one of Xu or X₄ is or comprises-P_P or -L-P_p or one of X₂ or X₃ comprises -P_p or -L-P_p, X_x is -OH, X₂ is -NH-CO-Y3 Y₃ is (i) a branched or unbranched C₈ to C₁₂ alkyl or alkenyl, preferably a C₉ alkenyl or a C_n alkyl, more preferably non-3-en-yl (T eicoplanin A₂- 1 ) , 7-methyl-octanyl (Teicoplanin A₂- 2), nonyl (Teicoplanin A₂-3), 7-methyl-nonyl (Teicoplanin A₂-4), 8-methyl-nonyl (Teicoplanin A₂-5); or (ii) a branched or unbranched C₃ to C19 alkyl or alkenyl, preferably a branched or unbranched C₅ to C₁₇ alkyl or alkenyl, more preferably a C₅ to C₁₇ alkyl, most preferably a C₉ to C_n alkyl X₃ is -NH₂, ¾ is H, X₅ is N-actylglucosamine, X₆ is Cl, X₇ is Cl, X₈ is H, X₉ is a-D- mannose, X₁₀ is, X_nare connected via a diphenylether, wherein each phenyl residue is preferably substituted one or more times with -OH, and X₁₂ is-CH₂-OH. Structure (P)

Element Wy

In a preferred embodiment element W 1 is selected from -P_p or— L-P_p. P_p is the polypeptide according to the present invention and L is said linker.

In a preferred embodiment, the N-terminus of the polypeptide P_p comprised in element W 1 is not attached to a lipophilic group.

In a preferred embodiment, the lipophilic group is not attached to any other position of the polypeptide P_p comprised in element W_x including, but not limited to, the C-terminus and side chains of the polypeptide.

In a more preferred embodiment element Wf is selected from— L-P_P. P_P is the polypeptide according to the present invention and L is said linker. Polypeptide:

The inventors surprisingly found that the polypeptide of the present invention enables the antibiotic structure modified by the polypeptide to overcome a mechanism of resistance towards the unmodified antibiotic. Without wishing to be bound by theory the inventors believe that the Antibiotic-polypeptide conjugates are not prone to common mechanisms of resistance against antibiotics such as vancomycin. The conjugates are antimicrobial active against bacteria with antibiotic resistances such as VanA, VanB and VanC types of resistance. Even against intrinsic vancomycin resistant bacteria like Lactobacillus pentosus, the antibiotic conjugates are sensitive. This suggests that the conjugates have an additional mode of action, compared to the unmodified antibiotic. Compared to vancomycin the results of MBC-testing of conjugates revealed a faster bactericidal mechanism of action (figure 9). Furthermore, fluorescence staining with D API/PI showed, that after treatment with the conjugates much more bacteria are dead and perforated compared to vancomycin (figure 1). The inventors believe that the antibiotic conjugates of the present invention play a role in the early steps of cell wall synthesis, possibly similar to the mode of action of ramoplanin.

In a preferred embodiment of the antibiotic of the second aspect of the present invention the polypeptide comprises 2 to 30, preferably 2 to 15, more preferably 2 to 10, most preferably 3 to 10, positively charged amino acid residues.

A positively charged amino acid has at a physiologic pH (pH 5-8) a positively charged side chain. Examples of positively charged proteinogenic amino acids include arginine, lysine and histidine. Non-proteinogenic amino acids can also be used in the present invention as long as the amino acids are positively charged. Non-limiting examples of suitable non-proteinogenic amino acids are a-aminoglycine, ornithine, 4,5-dehydrolysine, homoarginine, 4-aminophenylalanine and 3 -aminotyrosine.

In a more preferred embodiment of the antibiotic of the second aspect of the present invention the polypeptide comprises 2 to 30, preferably 2 to 15, more preferably 2 to 10, most preferably 3 to 10, lysine and/or arginine residues.

In a preferred embodiment of the antibiotic of the first or second aspect of the present invention the polypeptide is linear or circular, preferably linear, and:

(i) has a length of between 3 and 15 amino acids, preferably a length of between 3 to 12 amino acids, more preferably 3 to 8 amino acids; and/or

(ii) comprises at least 3, preferably at least 4, at least 5 or at least 6 positively charged amino acid residues, preferably arginine residues and/or lysine residues, in particular arginine residues; and/or (iii) comprises or consists of the following amino acid sequence: RRRRRR (SEQ ID NO: 1); RRRRR (SEQ ED NO: 2), RRRR (SEQ ID NO: 3), RRR, RRRRRRR (SEQ ID NO: 4), RRRRRRRR (SEQ ID NO: 5), RRRRRRRRR (SEQ ID NO: 6), RRRRRRRRRR (SEQ ID NO 7), R RR RRRRRR (SEQ ID NO: 8), RRRRRRRRRRRR (SEQ ED NO: 9), RRRRR C (SEQ ID NO: 10); RRRRRC (SEQ ED NO: 11), RRRRC (SEQ ID NO: 12); RRRC (SEQ ID NO: 13), RRRRRRRC (SEQ ID NO: 14), RRRRRRRRC (SEQ ID NO: 15), RRRRRRRRRC (SEQ ID NO: 16), RRRRRRRRRRC (SEQ ID NO 17), RRRRRRRRRRRC (SEQ ID NO: 18), RRRRRRRRRRRRC (SEQ ED NO: 19); RRK, RKR, RKK, KRK, KKR, RRRK (SEQ ID NO: 20), RRKR (SEQ ID NO: 21), RKRR (SEQ ED NO: 22), KRRR (SEQ ID NO: 23), RRKK (SEQ ID NO: 24), RKRK (SEQ ED NO: 25), KRKR (SEQ ID NO: 26), RKKR (SEQ ID NO: 27), KKRR (SEQ ID NO: 28), KRRK (SEQ ID NO: 29), KKKR (SEQ ID NO: 30), KKRK (SEQ ED NO: 31), KRKK (SEQ ID NO: 32), RKKK (SEQ ID NO: 33), KKKK (SEQ ID NO: 34), RRRKK (SEQ ID NO: 35), RRRKKK (SEQ ID NO: 36), CRRR (SEQ ID NO: 37), CRRRR (SEQ ID NO: 38); CRRRRR (SEQ ID NO: 39), CRKRRRR (SEQ ID NO: 40); CRRRRRRR (SEQ ED NO: 41), CRRRRRRRR (SEQ ED NO: 42), CRRRRRRRRR (SEQ ED NO: 43), CRRRRRRRRRR (SEQ ED NO: 44), CRRRRRRRRRRR (SEQ ID NO: 45), CRRRR RRRRRRR (SEQ ID NO: 46), KKKKKKC (SEQ ID NO: 47), RRRKKKC (SEQ ED NO: 48), RRRKKKC (SEQ ID NO 49), WWWRRRC (SEQ ED NO: 50), RRRGPRRRC (SEQ ED NO: 51), WRRLRRRVRC (SEQ ED NO: 52), RRWWRWWC (SEQ ED NO: 53), KRWWKWWC (SEQ ID NO: 54), CYRRRRRR (SEQ ID NO: 55) and CRRRRRRY (SEQ ED NO:56); optionally wherein the carbonyl-group of C -terminal cysteines is substituted by a carboxamide group and/or

(iv) additionally comprises one or more amino acids selected from the group consisting of Dab, C, A, G, or K and/or

(v) has a positive net charge of at least +2, preferably of at least +3, preferably of at least +4, preferably of at least +5, or more preferably of at least +6.

In a preferred embodiment the polypeptide comprises a C-terminal cysteine residue, wherein the carbonyl-group of said C-terminal cysteines is substituted by a carboxamide group. Such a

modified cysteine residue has the following structure , wherein the bond shown in the amino group is connected to the remaining amino acids of the polypeptide and the sulfur is connected to the linker if present or the antibiotic core. It is further preferred that the polypeptide consists of 3 to 10 amino acids and comprises between 3 to 8 arginine residues, preferably 3, 4, 5, 6, 7 or 8, most preferably 6. More preferably that the polypeptide consists of 4 to 8 amino acids and comprises between 3 to 8 arginine residues, preferably 3, 4, 5, 6, 7 or 8, most preferably 6. In the most preferred embodiment the polypeptide consists of 6 arginine residues.

In another preferred embodiment the polypeptide comprises or consists of RRRRRR (SEQ ID NO: 1).

In another preferred embodiment the polypeptide comprises or consists of CRRRRRR (SEQ ID NO: 40).

In another preferred embodiment the polypeptide comprises both arginine and lysine. Preferably, the same number of arginine and lysine residues. Accordingly, preferred peptides comprise or consist of 1 R and 3 K, 2 R and 2 K, 3 R and 1 K, 1 R and 4 K, 2 R and 3 K, 3 R and

2 K, 4 R and IK, 1 R and 5 K, 2 R and 4 K, 3 R and 3 K, 4 R and 2 K, 5 R and 1 K, in particular

3 K and 3 R.

An N- or C-terminal Cys residue facilitates coupling of the peptide.

In another preferred embodiment the polypeptide further comprises a tyrosine, preferably D- tyrosine. This is particularly advantageous for labelling with radioactive isotypes of iodine (e.g.

¹²⁵I).

The polypeptide of the present invention is coupled directly to the structure of the antibiotic or is coupled to a linker.

In a preferred embodiment of the antibiotic of the first or second aspect of the present invention, the polypeptide is coupled to a linker.

In a preferred embodiment of the antibiotic of the first or second aspect of the present invention the antibiotic or the linker is coupled to the N- or C-terminal amino acid of the polypeptide or to the side chain of an amino acid of the polypeptide, preferably an internal amino acid of the polypeptide.

In a preferred embodiment of the antibiotic of the first or second aspect of the present invention the linker or the polypeptide is conjugated to:

(i) a primary or secondary amine of the antibiotic, preferably forming a peptide bond between antibiotic and the linker or the polypeptide;

(ii) a carboxylgroup of the antibiotic, preferably forming a peptide bond or an ester bond between the antibiotic and the linker or the polypeptide;

(iii) a hydroxyl group of the antibiotic, preferably forming an ester bond or ether bond between the antibiotic and the linker or the polypeptide. In a preferred embodiment the antibiotic of the first or the second aspect of the present invention comprises 1, 2, 3 or 4 polypeptides P_p.

In a more preferred embodiment the antibiotic of the first or the second aspect of the present invention comprises 1 or 2 polypeptides P_P.

In a most preferred embodiment the antibiotic of the first or the second aspect of the present invention comprises 1 polypeptide P_p.

In a preferred embodiment the antibiotic according to the first or the second aspect of the invention comprises one polypeptide P_p, which is attached to element X_j of structure (I) as part of -P_p or -L-P_p as indicated for _x of structure (I).

In a preferred embodiment the antibiotic according to the first or the second aspect of the invention comprises one polypeptide P_p, which is attached to element X₂ of structure (I). In this embodiment the polypeptide P_P is part of Y₉ as defined above.

In a preferred embodiment the antibiotic according to the first or the second aspect of the invention comprises one polypeptide P_P, which is attached to element X₃ of structure (I). In this embodiment the polypeptide P_P is part of X₁₄ or X_15.

In a preferred embodiment the antibiotic according to the first or the second aspect of the invention comprises one polypeptide P_p, which is attached to element X₄ of structure (I) as part of -P_P or -L-Pp as indicated for X₄ of structure (I).

In a preferred embodiment a polypeptide P_p is attached to each of the elements X_! and X₃ of structure (I). The polypeptide P_p is attached to element X₃ of structure (I) as part of X₁₄ or X₁₅ and the second polypeptide P_p is attached element X₃ as part of -P_p or -L-P_p as indicated for Xi of structure (I).

In a preferred embodiment the polypeptide P_P is attached to element Wi of structure (P) as part of -P_p or -L-P_P as indicated for Wi of structure (I).

Linker:

Without wishing to be bound by theory the inventors believe that the linker is mainly involved in determining the organ distribution of the antibiotic. For example the use of a linker with a higher lipophilicity will direct the conjugate to the liver. The use of PEGylated linkers can achieve a prolonged retention time in the bloodstream.

In a preferred embodiment of the antibiotics of the first or second aspect of the present invention the optional linker also designated“L” when present is selected from the group consisting of: etkylenediamine, SMCC (succinimidyl 4-(N-maleimidomethyl)cyclohexane- 1 - carboxylate), succinimidyl-([N-maleimidopropionamido]-(ethyleneglycol)_n)ester, wherein n is an integer between 1 to 10, preferably the linker is ethylenediamine and/or SMCC, most preferably the linker is SMCC.

In a preferred embodiment of the antibiotics of the first or second aspect of the present invention the optional linker may comprise two or more of the disclosed linkers coupled to each other. Non limiting examples would be a combination of ethylenediamine with SMCC or siiccinimidyl-([N-maleimidopropionamido]-(ethyleneglycol)_n)ester, wherein n is an integer between 1 to 10.

In a preferred embodiment of the antibiotics of the first or second aspect of the present invention the optional linker also designated“L” when present is selected from the group consisting of:

-O(CR₂₀R₂₁)_m(CR₂₂R₂₃)_n(OCH₂CH₂)_p(CR₄₀R₄₁)_P»Y”(CR₂₄R₂₅)_q(C=O)_tX"

-O(CR₂₀R₂₁)_ra(CR₂₂R₂₃)_n(OCH₂CH₂)_p(CR₄₀R_4i)_P»Y"(CR₂₄R₂₅)_q(NH)_tX'',

-0(CR₂₀R₂₁)_m(CR₂₂R₂₃)_n{OCH₂CH₂)_p(CR₄oR_4i)_P'Y"(CR₂₄R₂₅)_qX"

-O(CR₂₀R₂₁)_m(CR₂₆=CR₂₇)_m<CR₂₂R₂₃ OCH₂CH₂)_p{CR₄₀R_4i)_p»Y''(CR₂₄R₂₅)_q{C=O)_tX",

-0(CR₂₀R₂₁)_m(CR_2ff=CR₂₇)_m<CR₂₂R₂₃)_I1(OCH₂CH₂)_p{CR₄oR_4i)_P'Y"(CR₂₄R₂₅)_q(NH)_tX"₅

-0(CR₂oR₂₁)_ni(CR_2e=CR₂₇)_m.(CR₂₂R₂₃)_n(OCH₂CH₂)_p(CR₄oR_4i)_p«Y"(CR₂₄R₂₅)_qX",

-O(CR₂₀R₂₁)_m(alkyiiyl)_n<CR₂₂R₂₃)_n(OCH₂CH₂)_p(CR_4OR₄₁)_p«Y"(CR₂₄R₂₅)_cl(C=O)tX",

- O (CR₂₀R₂ I )_m(pip erazino)_t-(C ₂₂R₂₃)_n(OCH₂CH₂)_p(CR4o 4 i)_r>Ύ " (C R₂₄R₂₅)_q(C=G)_tX " ,

-O(CR₂₀R₂₁)_m(piperazmo)_t<CR₂₂R₂3)_n(OCH₂CH₂)_p(CR₄₀R₄₁)_p-Y^,'{CR₂₄R₂₅)_q(NH)_tX",

-O(CR₂₀R₂₁)_m(piperaziiio)_t<CR₂₂R₂₃)_n(OCH₂CH₂)_p(CR₄₀R_4i)_p.Y^r"(CR₂₄R₂₅)_qX",

-O(CR₂₀R₂₁)_ni(pyiTolo)_t<CR₂₂R₂₃)_n(OCH₂CH₂)_p(CR₄₀R_4i)_I,Y''(CR₂₄R₂₅)_q(C=O)_tX",

-O(CR₂₀R₂₁)_m(pynOlo)_t<CR₂₂R₂₃)_n(OCH₂CH₂)_p(CR₄₀R_4i)_pY"(CR₂₄R₂₅)_q(NH)_tX",

-O(CR₂₀R₂₁)_m(pynOlo)_t-(CR₂₂R₂3)_n(OCH₂CH₂)_p(CR₄₀R4₁)_p.Y"(CR₂₄R₂₅)_qX",

-O(CR₂₀R₂₁)_ffiA"_m-(CR₂₂R₂₃)_n(OCH₂CH₂)_p(CR₄₀R₄₁)_pnY"(CR₂₄R₂₅)_q(C^O)_tX",

-O(CR₂₀R₂₁)_mA"_m-(CR₂₂R₂₃)_n(OCH₂CH₂)_p(CR₄₀R₄₁)_p,Y^f'(CR₂₄R₂₅)_q(NH)_tX",

-0(CR₂₀R₂₁)_mA"_m»(CR₂₂R₂₃)_D(OCH₂CH₂)_p(CR₄oR_4i)_p-Y"{CR₂₄R₂₅)_qX",

-S(CR₂₀R₂₁)_m(CR₂₂R₂₃)₁₁(OCH₂CH₂)_p(CR₄₀R₄₁)_p.Y"(CR₂₄R₂₅)_q(C=O)_tX",

-S(CR₂₀R_2i)_m(CR₂₆=CR₂₇)_ni<CR₂₂R₂₃)₁₁(OCH₂CH₂)_p(CR₄oR_4i)_p'Y"(CR₂₄R₂₅)_q(C=0)_tX'',

-S(CR₂₀R_2i)_ia(CR₂₆=CR₂₇)_m<CR₂₂R₂₃MOCH₂CH₂)_p(CR₄₀R_4i)_p'Y"(CR₂₄R₂₅)_q(NH)_tX",

-S(CR₂₀R2i)_m(CR₂₆=CR2₇)_m<CR₂₂R₂₃)_n(OCH2CH2)_p(CR4oR4i)_P ^»Y"(CR₂₄R₂₅)_qX"

-S(CR₂₀R₂₁)_m(alk>iiyl)_I1<CR₂₂R₂3)_n(OCH₂CH₂)_p(CR₄₀R₄₁)_p-^,Y"(CR₂₄R₂₅)_q(C=O)_tXⁿ, -S(CR₂₀R₂₁)_m(aliFiyl)_il<CR₂₂R₂3)_n(OCH₂CH₂)_p(CR₄₀R₄₁)_p»Y"(CR₂₄R₂₅)_q(NH)_tX",

-S(CR₂₀R₂₁)_m(alk>iiyl)_a<CR₂₂R₂₃)_n(OCH₂CH₂)_p(CR₄₀R₄₁)_P'-Y"(CR₂₄R₂₅)_qX'',

-S(CR_2{)R₂₁)_I11(pipera.zi]io)_t'(CR₂₂R₂₃)_n(OCH₂CH₂)_p(CR₄oR_4i)_p»Y''(CR₂₄R₂₅)_q(C=0)_tX",

-S(CR₂₀R₂₁)_m(piperaziiio)_t<CR₂₂R₂3)_n(OCH₂CH₂)_p(CR4₀R4i)_P»Y"(CR₂₄R₂5)_q(NH)_tX",

-S(CR₂₀R₂₁)_m(pipera.ziiio)_t<CR₂₂R₂3)_I1(OCH₂CH₂)_p(CR₄₀R₄₁VY"(€R₂₄R₂₅)_qX"₃

-NR₃₃(C=0)_p,(CR₂₀R₂₁)_m(alkyiiyl)_n<CR₂₂R₂₃)_n(OCH₂CH₂)_p(CR₄oR_4i)_P-Y"(CR₂₄R₂₅)_q-(NH)_tX", -NR₃₃(C=0)_p.<CR₂₀R₂₁)₁₁₁(alkyiiyl)_D<CR₂₂R23)_n(OCH₂CH₂)_p(CR₄oR4i)p_"Y"(CR₂₄R₂₅)_qX'^, _!

-N 3₃(C=0)p_"(CR₂o _2i)_m(piperaziiio)t_'(C _{22 23})_n{OCH₂CH₂)p(CR4oR4i) _'Y”(CR₂₄R₂₅)q- fO=Q)_tX",

-NR₃₃ (C=0)_p- (CR₂₀R_{2 i})_m(pip erazino)_t'(CR₂2R23)_n(OC H₂C H₂)_p(CR₄oR₄ i)_rΎ” (CR₂₄R₂₅)_q-

(NH)_tX",

(€=0)_tX",

-NR₃₃(C=0)_p»(CR₂oR₂₁)_ni(pynOlo)_f(CR₂₂R₂₃)_n(OCH₂CH₂)_p(CR₄₀R₄₁)_p»Y"(C _{24 25})_q— (NH)_tX", -NR₃₃(C=O)_p CR₂₀R₂₁)_m(pynOlo)_r(CR₂2R23)_n(OCH₂CH₂)_p(CR₄₀R₄₁)_p»Y"(CR₂₄R₂₅)_qX", -NR₃₃(C=0)_p»(CR₂oR_2i)_m(C₄-C₇-cycloalkyl)_t'(CR₂₂R₂₃)_a(2 ,5- dioxopynOlidiiiyl)_p(CR₂₄R₂₅)_p-(C=0)_tX",

-NR₃₃(C=0)_P"(CR₂oR_2i)_m(C₄-C₇-cycloalkyl)_t'(CR₂₂R₂₃)_n(2,5- dioxopyiTolidinyl)_p(CR₂₄R₂5)_p-(NH)_t X" , -NR₃₃(C=O)p, CR₂₀R2i)_m(C4-C₇-cycloalkyl)t<CR₂₂ 23M2,5-dioxopynOliilmyl)p(CR24R25)p"X",

-NR₃₃(C=0)_p»(CR_2£)R₂₁)_mA"_ni-<CR₂₂R₂₃)_n(OCH₂CH₂)_p(CR₄oR_4i)_p»Y''(CR₂₄R₂₅)_tl(C=0)_tX",

-(C=O)_p ^»(C ₂₀ 2₁)_m(C ₂₆^R27)_m<C 22R23)_n(OCH₂CH₂)_p(CR4₀ 4₁)_p ^»Y"(C ₂₄ 25)_q-X"

-(C=0)_p.(CR₂₀R₂₁)_m(alkyiiyl)_n<CR₂₂R₂₃)_n(OCH₂CH₂)_p(CR₄oR_4i)_P-Y"(CR₂₄R₂₅)_il-( C=0)_tX",

.(C=0)_p.(CR₂o _2i)_m(alkyiiyl)_Ii<C ₂₂R₂₃)_Ii(OCH₂CH₂)_p(C:R_{40 4i})_p-Y"(CR_{24 25})_q-(NH)_tX",

^„(C=0)_p ^»(CR2o _2i)m(alkynyl)_n<CR22 23)₁(OCH2CH2)p{C 4o 4i)_P*Y"(C _{24 25})_q ",

.(C=O)_p-(CR₂₀R2i)_m{piperazmo)_t<CR₂₂R₂₃)_n(OCH₂CH₂)_p(CR4₀R4i)_P-Y"(CR24R₂5)_q-( C=O)_tX",

-(C=O)_p»{CR₂₀R₂₁)_m(piperaziiio)_t<CR₂₂R₂₃)_I1(OCH₂CH₂)_p(CR₄₀R₄₁)_p»Y"(CR24R25)_q-(NH)_tX”,

-(C=O)_p»(CR₂₀R₂₁)_m{Piperaziiio)_t<CR₂₂R₂₃)_I1(OCH₂CH₂)_p(CR₄₀R₄₁)_p»Y"(CR₂₄R₂₅)_tlX",

-(C=0)_p»{CR_2(}R₂₁)_in(pyiTolo)_t<CR₂₂R₂₃)_I1(OCH₂CH₂)_p(CR₄₀R₄₁)_p»Y"(CR₂₄R₂₅) _! ( C=0)_tX",

-(C=O)_p»(CR₂₀R₂₁)_m{pynOlo)_t<CR₂₂R₂3)_n(OCH₂CH₂)_p(CR₄₀R₄₁)_p.Y"(CR24R25)_q-(NH)_tX"₅

-(C=O)_p»(CR₂₀R₂₁)_m{pyiTolo)_t<CR₂₂R₂₃)_I1(OCH₂CH₂)_p(CR₄₀R4₁)_p.Y"(CR₂₄R₂₅)_qX",

- (C=0)_p»(CR₂oR_{2 l})_m(C₄- C ₇ -eye loalky l)_f (CR₂₂R₂₃)_n(2 , 5 - dioxopynOlidiiiyl)_p(CR₂₄R₂₅)_p..(C=0)_tX",

-(C=0)_p.(CR₂oR_2i)_m(C₄-C₇-cyclOalkyl)_t<CR₂₂R₂₃)_n(2_;5-(!ioxopynOlidinyl)_p(CR₂₄R₂₅)_p-(NH)_t X", -(C=0)p^«(CR₂oR_2i)_m(C4-C₇-cycloaltyl)r(CR₂₂R₂₃)_n(2,5-dioxopynOlidiiiyl)p(CR₂₄R25)p^»X", -(C=0)_p.(CR₂oR_2i)_aiA"_m™(CR₂₂R₂₃)_I1(OCH₂CH_{2 )p(} CR40R41 y Y"( CR₂₄R₂₅)_q( C=0)_t X",

-(C=O)_p»(CR₂₀R₂₁)_mA"_m CR₂₂R₂₃)_n(OCH₂CH₂ )_p( CR^yY”! CR₂₄R_{25 )q(}NH)_tX".

-(C=O)_p»{CR₂₀R₂₁)_I11A"_m"(CR₂₂R₂₃)_I1(OCH₂CH_{2 )p(} CR₄oR₄₁)_p''Y"( CR₂₄R₂₅)_qX".

-(CR₂₀R₂₁)_ni(CR₂₂R₂₃)_n(OCH₂CH₂)_p{CR₄oR₄₁)_p,Y''(CR₂₄R₂₅) ₁(C=0)_tX",

-(CR₂₀R₂₁)_m(CR₂₂R₂₃)_n(OCH₂CH₂)_p(CR₄₀R₄₁)_p»Y"(CR₂₄R₂₅)₁(NH)_tX'',

-(CR₂₀R₂₁)_m(CR₂₂R₂₃)_n{OCH₂CH₂)_p{CR₄₀R₄₁)_p™Y"(CR₂₄R₂₅)_qX",

-(CR₂oR2_l)_nl(CR26=CR2₇)_m<CR22R23)_Ii(OCH2CH₂)_p(CR4oR4_l)_P"Y"(CR₂₄R₂₅)_qX"

-(CR₂₀R₂₁)_m(alk}Tiyl)_I1.(CR₂₂R₂₃MOCH₂CH₂)_p(CR₄₀R_4i)_P»Y"(CR₂₄R₂₅)_q(C=O)_tX",

-(CR₂₀R_2i)_m(alkyiiyl)_n-(CR₂₂R₂₃MOCH₂CH₂)_p(CR₄₀R_4i)_P»Y"CCR₂₄R₂₅)_q(NH),X"

-(CR₂₀R₂₁)_m(alkynyl)_I1.(CR₂₂R₂₃)_I1(OCH₂CH₂)_p(CR₄₀R₄₁)_p»Y"(CR₂₄R₂₅)_qX", -(CR₂₀R₂₁)_ni(pipexaziiio)_t<CR₂₂R₂₃)_n(OCH₂CH₂)_p(CR₄₍₎R₄₁)_p»Y"(CR₂₄R₂₅)_q(C=0)_tX",

-(CR₂₀R₂₁)_m(pip€raziiio)_t<CR₂₂R₂₃)_n(OCH₂CH₂)_p(CR₄₀R₄₁)_P'-Y"(CR₂₄R₂₅)_q(NH)_tX"

(CR₂₀R₂₁)_m(piperazino)_r(CR₂₂R₂₃) (OCH₂CH₂)_p(CR₄oR_4i)_P"Y"(CR₂₄R₂₅)_qX",

-(CR₂oR₂₁)_niA"_m.(CR₂₂R₂₃)_n(OCH₂CH₂)_p(CR₄₀R_4i)_p»Y"(CR₂₄R₂₅)_q(C=X⁾)_tX",

(C=0)_tX",

-(CR₂₀R₂₁)_ni(CR₂₉N-NR3₀)_n.(alkyiiyl)_I1<CR₂₂R₂₃)₁₁(OCH₂CH₂)_p(CR4oR4i)_P-Y"(CR₂₄R₂₅)_q-{NH)_tX",

-(CR₂₀R₂₁)_m(CR₂₉N-NR3₀)_n<alkyiiyl)_B<CR₂₂R2₃)_n(OCH₂CH₂)_p(CR₄₀R₄₁)_p.Y"(CR₂₄R₂₅)_q-X",

-(CR₂₀R₂₁)_ni(CR₂₉=N-NR₃₀)_n.A"_m'<CR₂₂R₂₃)_n(OCH₂CH₂)_p(CR₄₀R₄₁)_p.Y"(CR₂₄R₂₅) {C=O)_tX"₃

-(CR₂₀R₂₁)_ni(CR₂₉^N-NR₃o)_n»A"_m.<CR₂₂R₂₃)_n(OCH₂CH₂)_p(CR₄oR4i)_p.Y"(CR₂4R25)_q-(NH)_tX”,

-(CR₂₀R₂₁)_m(CR₂₉=N-NR₃₀)_n.A"_m<CR₂₂R2₃)_n(OCH₂CH₂)_p(CR4₀R4i)_P-Y"(CR₂₄R25)q-X", preferably -(C=0)_p.{CR₂oR_2i)_m(C₄-C₇-cycloalkyl)_t<CR₂₂R₂₃)_!1(2,5- dioxopynOlidiiiyl)_p(CR₂₄R₂₅)_p»X", -NR₃₃(C=0)_p«(CR₂oR_2i)_m(C₄ C₇-eycloalkyl)_t<CR₂₂R₂₃)_n(2,5- dioxopynOlidiiiyl)_p(CR₂₄R₂5)_p»X",

wherein:

m, ii, p, q, in', n', f for each occurrence are independently are integer from 1 to 10, 2 to 9, 3 to 8 or are optionally 0;

t, in", n" and p" for each occurrence are independently are 0 or 1 ;

X” is a bond to P_p or a bond to a cysteine, preferably the sulphur group of said cysteine, wherein the cysteine is bound to P_p, optionally the carbonyl- group of said cysteine is substituted by a carboxamide group;

or

when Y" is not S— S and t=0, X" is selected from a maleimido group, a haloacetyl group or SR₃₇, wherein R₃₇ has the same definition as above; A" is an amino acid selected from glycine, alanine, leucine, valine, lysine, eitmlline and glutamate or a polypeptide containing between 2 to 20 amino acid units;

R-20, R_2I, R-22, R₂₃, R2_% R₂₅, R₂₆, and R₂₇ are the same or different and are H or a linear or branched alkyl having from 1 to 5 carbon atoms;

R₂9 and R₃₀ are the same or different and are H or alkyl from 1 to 5 carbon atoms;

R₃₃ is H or linear, branched or cyclic alkyl, alkenyl or alkynyl having from 1 to 12 carbon atoms, a polyethylene glycol unit— (OCH₂CH₂)_n, or R₃₃ is— COR₃₄,— CSR₃₄,— SOR₃₄, or— SG₂R_34, wherein R₃₄ is H or linear, branched or cyclic alkyl, alkenyl or alkynyl having from 1 to 20 carbon atoms or, a polyethylene glycol unit— (OCH₂CH₂)_n; and

one of R40 and R_4J is optionally a negatively or positively charged functional group and the other is H or alkyl, alkenyl, alkynyl having 1 to 4 carbon atoms.

In a preferred embodiment the antibiotic comprises a structure according to formula (I), the linker is -(C=O)_p»(CR₂₀R_2i)_m(C4-C₇-cycloalkyl)_t CR₂₂R₂3)_n(2 ,5 - dioxopyiTolidmyl)p(CR₂₄R₂₅)p_"X".

In a preferred embodiment the antibiotic comprises a structure according to formula (P), the linker is -NR₃₃(C=O)_p.(CR₂₀R_2i)_m(C₄-C₇-c cloalkyl)_t<CR_{22 23})_I1(2,5- dioxopyirolidmyl)_p(CR₂4R₂₅)_p-X".

Antibiotics:

In a preferred embodiment of the antibiotics of the first or second aspect of the present invention the antibiotics have one or more of the following properties:

(i) a minimal inhibitory concentration (MIC) that is at least 50% lower than the MIC of the respective antibiotic without the coupled polypeptide; preferably for antibiotics with a vancomycin core of 8 mg/L or less against E. faecium VanA UL602570, E. faecium VanA UL407074, E.faecalis VanO ATCC292I2, E.faecalis VanB SC413687, E.faecalis VanB ATCC 51299, E. faecium VanB UL405955, E. casseliflavus VanC ATCC 700327 and E. gallinamm VanC AL405773;

(ii) a cytotoxicity against human peripheral blood mononuclear cells (PBMCs) of less than 10% at the MIC;

(iii) a reduced kidney accumulation;

(iv) a plasma half-life that is at least 50% longer than the respective antibiotic without the coupled polypeptide and linker if present.

In a more preferred embodiment of the antibiotics of the first or second aspect of the present invention the antibiotics have one or more of the following properties: (i) a minimal inhibitory concentration (MIC) that is at least 50% lower than the MIC of the respective antibiotic without the coupled polypeptide; preferably for antibiotics with a vancomycin core of 8 mg/L or less against E. faeciurn VanA UL602570, E. faecium VanA UL407074, E. faeealis VanO ATCC29212, E. faecalis VanB SC413687, E.faecalis VanB ATCC 51299, E. faecium VanB UL405955, E. casseliflavus VanC ATCC 700327 and E. gallinarum VanC AL405773;

(iii) a plasma half-life that is at least 50% longer than the respective antibiotic without the coupled polypeptide and linker if present

(iv) a cytotoxicity against human liver cells of less than 10% at the MIC, preferably less than 10% cytotoxicity at 64 pg/ml;

(v) a cytotoxicity against human kidney cells of less than 10% at the MIC, preferably less than 10% cytotoxicity at 64 pg/ml.

The antibiotic sensitivity which refers to the resistance of bacteria against an antibacterial compound is determined as known in the art, for example by in vitro cultivation of isolated bacteria in the presence or absence of different antibiotics and different concentrations thereof. Bacterial strains can be defined regarding their antibiotic resistance by an antibiogram, which commonly refer to the MIC of the tested antibiotics. Antibiotic sensitivity can be measured by a Vitek-2 system (bioMerieux) according to the manufacturer’s instructions. Determination of resistance gene is performed by PCR as described in Klein et al. (Journal of Medical Microbiology (2012), 61, 323-331).

Biodistribution (e.g. liver, kidney etc. accumulation) of the antibiotics of the invention can be measured as known in the art, for example by biodistribution studies as described in (Wischnjow et al., Bioconjugate chemistry 27.4 (2016): 1050-1057).

Use of the antibiotics:

In a third aspect of the present invention the antibiotics of the first or second aspect is for use in the treatment or prophylaxis of a bacterial infection.

In a preferred embodiment of the antibiotics for use according to the third aspect of the present invention the bacterial infection is with a bacterium selected from the group consisting of a gram negative and gram positive bacterium, preferably a vancomycin-resistant bacteria, in particular Enterococci, Staphylococci, or Streptococci. In a preferred embodiment of the antibiotics for use according to the third aspect of the present invention, the bacterial infection is with a multiple drug resistant bacterium (MRSA), e.g. VRE, preferably Staphylococci, E.faecium, E.faecalis, 01 Έ. gallinarum.

In a preferred embodiment of the antibiotics for use according to the third aspect of the present invention the antibiotic is used in combination with one or more antibiotics selected from the group consisting of glycopeptides, tetracyclines, aminoglycosides, and cephalosporines.

EXAMPLES

The following protocols for synthesis of the compounds uses the nomenclature provided in scheme 1. V_c corresponds to substituent X_j in structure (I), V_v to substituent X₂, V_N to substituent X₃ and V_R to substituent X4.

Scheme 1: Nomenclature of modification sites in vancomycin

Example 1: Synthesis of the V_R-position

BB-2041 [Scheme 2] was synthesized from vancomycin · HC1, formaldehyde and ethylene diamine according to Long et al. [19] and purified by preparative HPLC afterwards.

Scheme 2: Synthesis of BB-2041

A solution of 5 mg BB-2041 in 100 mΐ PBS (pH 8.17) was mixed with a solution of 1 g

BB-2036, stirred and purified by HPLC after 2 days.

Scheme 3: Reaction of BB2041 with BB-2036

Example 3: Synthesis of the Vy-ethylenediamme derivative

For the synthesis of BB-2051 (Scheme 4) vancomycin · HC1, N-(9-fluorethoxycarbonyl) glycinal was used as described by Long et al. [20] and purified afterwards by preparative HPLC.

Scheme 4: Synthesis of BB-2051

The product was deprotected with quinuclidine as described by Long et al. [20] and used without further purification.

For the coupling of the SMCC-iinker (scheme 5), 5 mg BB-2054 in 200 mΐ of a PBS (pH 8.17) solution was mixed with a 20 mg/ml Sulfo-SMCC in DMSO solution. After 30 min the mixture was purified by HPLC. The yield of the reaction was 3.7 mg.

Scheme 5: Coupling of SMCC-linker Example 4: Synthesis of the vancomycin V_N-ethylenediamine derivative

BB-2057 was synthesized according to Griffin et al. [21] using vancomycin HC1 and N-(9- fluorenthoxycarbonyl)glycinal and purified by preparative HPLC (see scheme 6).

Scheme 6: Synthesis of BB-2057 The product was deprotected with quinuclidine as described by Griffin et al. [21] and used without further purification.

For the synthesis of the Vancomycin- V_N-ethylenediamine-derivative (see scheme 7) 49.7 mg BB-2070 in 1 ml PBS pH 8.17.DMSO 1:1 was mixed with 10 mg Sulfo-SMCC in 100 mΐ DMSO solution. HPLC showed a ca. 70% reaction after 30 min. The solution was purified by preparative HPLC and the purified fraction was lyophilized. The yield of the reaction was 22.3 mg.

Scheme 7: Synthesis of the vancomycin-V^-ethylenediamine-derivative Example 5: Synthesis of the vancomycin V _c-ethylenediamine derivative

For the synthesis of BB-2072 (see scheme 8) vancomycin · HC1 (149 mg; 0.1 mmol) was dissolved in 1 ml DMSO andN-Ethyl-N-(propan-2-yl)propan-2-amine (DIPEA) (54 mΐ; 0.3 mmol) was added. To this mixture ethylene diamine (10 mΐ; 0.149 mmol) was added followed by a solution of Benzotriazol-l-ol (HOBt) (14.8 mg; 0.11 mmol) and PyAOP ((7-Azabenzotriazol-l- yloxy)tripyrrolidinophosphonium hexafluorophosphate) (58 mg; 0.11 mmol) in DMF (0.5 ml). After 2 hours, the mixture was purified by preparative HPLC and the purified fraction was lyophilized. The yield of the reaction was 97.5 mg.

Scheme 8: Synthesis of BB-2072 For the synthesis of the vancomycin- V_c-ethylenediamine-derivative a solution of 20 mg BB-

2072 in 400 mΐ PBS pH 8.17:DMSO 1:1 was added to a 4 mg Sulfo-SMCC in 40 mΐ DMSO solution. Verification by HPLC showed a ca. 70% reaction after 30 min. The purification was performed by preparative HPLC and the purified fraction was lyophilized. The yield of the reaction was 9 mg.

Scheme 9: Synthesis of the Vancomycin-Vc-ethylenediamine derivative

Example 6: Synthesis of the vancomycin V_N-SMCC-derivative (direct linking without ethylenediamine)

200 mg vancomycin HC1 were dissolved in 200 mΐ phosphate buffered saline (pH = 8.16) and mixed with 20 mΐ of a 0.046 mM Sulfo-SMCC in DMSO stock solution (see scheme 10). The mixture was shaken overnight at 40 °C and purified by preparative HPLC.

Scheme 10: Synthesis of the vancomycin VrSM CC-derivative

Example 7: Synthesis of the peptide

The peptides were synthesized using Fmoc-solid phase synthesis as described previously by Brings et al. [22] Therefore, a rink amid resin was loaded with 0.74 mmol cysteine per g resin. After automated coupling, using an Applied Biosystems 433 A synthesizer, the resin was washed with DCM and MP. The cleavage of the peptide was performed in a mixture of TFA/H₂0/TIS at a ratio of 90/5/5 for 4 hours with a following precipitation in diethyl ether and a centrifugation (3000 rpm, 5 min, two times). The purification of the peptides was performed on a Gilson 321 High-Performance Liquid chromatography (HPLC) system with a Reprosil Gold 120 C18 4 pm 150 x 120 mm column (Dr. Maisch, Ammerbuch, Germany). To identify the peptides a HPLC/MS using a Thermo Fisher Exactive Orbitrap System equipped with a Cl 8 column, (Hypersil Gold aQ, Thermo Scientific, USA) was used.

The coupling of the fatty acids was performed as described previously by Domhan et al. (Int J Antimicrob Agents. 2018 Jul;52(l):52-62). Therefore, 8 eq. of a fatty acid were dissolved in 1- methyl-2-pyrrolidinone (NMP). To the solution 8 eq. of the activation agent ( 1 -cyano-2-ethoxy- 2-oxoethylidenaminooxy)dimethylamino-morpholino-carbenium hexafluorophosphate (COMU) and 10 eq A_^A-diisopropylethylamine DIPEA (5.5 M) were added. After activation for 10 min the solution was added to the resin and coupled for at least 90 min. To purify the product, a HPLC was used as described previously.

Example 8: Coupling of the peptide to vancomycin-linker-con j ugate

The peptides were coupled to the vancomycin-linker-conjugate using PBS (adjusted to pH = 5.5) as conjugation buffer. Therefore, 128.74 mg of the vancomycin-V^-SMCC preliminary stage were solved in 7.9 ml PBS (pH = 5.5) and the relevant peptide (244 pmol in DMSO) was shaken at 40 °C overnight and purified by HPLC.

Scheme 11: Coupling of the peptide according to SEQ ID NO: 10 to vancomycin linker-conjugate

Example 9: Synthesis of Atto-vancomycin- V_N-SMCC-KR9C-derivative

For the synthesis of the Atto-labeled vancomycin-conjugate BB-2072 (6.71 pmol) were mixed with Sulfo-SMCC (10.2 pmol) in PBS (pH = 5.5) and coupled for 72 hours. The product was mixed with one equivalent of Atto-488 (Atto-Tec, Siegen Germany) in a Na₂C0₃-buffered solution (pH > 9). The mixture was shaken overnight at room temperature. The purification was performed by preparative HPLC.

The resulting Atto-V_c-vancomycin-V_N-SMCC was dissolved in PBS buffer (pH = 5.5) and mixed with the peptide KR₉C (1.4 pmol in DMSO) and shaken for 48 h. The pmification was performed by preparative HPLC. Example 10: Antimicrobial assay for determining Minimum Inhibitory Concentration

(MIC)

MICs were determined by microdilution according to CLSI guidelines [23, 24]. Briefly, Cation-adjusted Mueller-Hinton-Broth and vancomycin (potency 99.1%) were purchased from Sigma-Aldrich (Steinheim, Germany). For all tests polypropylene 96well plates (Sigma-Aldricli, Stein eim, Germany) were used. Antimicrobial substances were dissolved in water. For vancomycin-conjugates different concentrations were used. All other antibiotic-conjugates were used in dilutions ranging from 64 pg/ml to 31.25 ng/ml. Overnight cultures of bacteria were directly suspended, adjusted to a McFarland corresponding to 80.000.000 ± 60% cfii/ml bacteria with a DensiCHEK^® plus (Biomerieux, Marcy-l'Etoile, France) and afterwards diluted to 1 x 10⁶ cfii/mL and loaded on the 96well plates. After an incubation time of 16-20 hours the MIC was determined as the lowest concentration without visible growth (see Domlian et al, Int J Antimicrob Agents. 2018 Jul;52(l):52-62). For comparison all results were calculated in mol/mL afterwards.

The results plotted in figure 6 (left graph) are provided in table 1.

Table 1 MIC values frng/L] of figure 6 (left graph)

Example 11: Staining protocol for viability and cell membrane permeability of Bacillus megaterium A staining protocol based on Mangoni et al. was developed [25] Therefore, two dyes were used: (i) DAPI, as a membrane permeable dye to stain all bacteria (living and dead) by binding double-stranded DNA [26] and (ii) propidium iodide (PI) which also binds to DNA but cannot traverse intact cell membranes. Therefore, PI is a dye for staining dead bacteria with damaged membranes (Lecoeur, Exp Cell Res. 2002;277:1-14). For the staining, three colonies of an overnight culture of Bacillus megaterium DSM 32 were washed in phosphate buffered saline (PBS) and centrifuged at 4000 rpm for 5 min. The resulting pellet was resuspended in PBS. This procedure was repeated for at least two times. The resulting, washed bacteria were diluted in cation adjusted Mueller-Hinton Broth to a concentration of 10⁸ cfii/ml. 200 mΐ of the cell suspension were mixed with either 100 mΐ PBS as negative control or 100 mΐ of vancomycin or 100 mΐ of a conjugate. The conjugates and vancomycin were used in a concentration corresponding to 5x MIC. After 30 min incubation at 30 °C, 300 mΐ ofDAPI (Sigma-Aldrich, Steinheim, Germany) solution (1 mg/ml) was added and the mixture was incubated for 30 min at 30 °C. Afterwards, the suspension was centrifuged at 4000 rpm for 5 min and the supernatant was removed. 30 mΐ of PI solution (1 mg/ml), (Sigma-Aldrich, Steinheim, Germany) in 470 mΐ PBS were added and incubated for 10 min at 30 °C. The suspension was centrifuged at 4000 rpm for 5 min and the supernatant was removed. The resulting pellet was resuspended in 100 mΐ of PBS. 10 mΐ of the suspension were transferred on a poly-L-lysine coated glass slide (Sigma-Aldrich, Steinheim, Germany). Images were recorded with a Keyence BZ-9000 fluorescence microscope (Keyence Deutschland GmbH, Neu-Isenburg, Germany) at 1.000 x magnification with a Nikon CFI Plan Achromat l lOOx Oil (Nikon, Tokyo, Japan) under oil immersion. For fluorescence images a Keyence OP79304, DAPI-filter (emission 447/60 run, excitation 377/55 mn, dichro 409 nm) obtained from (Keyence Deutschland GmbH, Neu-Isenburg, Germany) respectively a Keyence OP79302 TxRed-filter (emission 624/40 nm. excitation 562/40 nm, dichro 593 nm) obtained from (Keyence Deutschland GmbH, Neu-Isenburg, Germany) were used. Image processing was performed with Keyence BZ-P Analyzer software, version 2.1.

For the vancomycin-conjugate coupled to Atto488 the cell suspension was mixed with 100 mΐ of the corresponding conjugate (FU002) in a 5x MIC concentration and 0.42 mg of the Atto-labeled conjugate. After 30 min incubation at 30 °C only PI was added and the suspension was incubated for further 10 min. The following steps were performed as described above.

Example 12: Radiolabeling of vancomycin derivatives

For radiolabeling of the tyrosine-modified derivatives of vancomycin, (yRRRRRRC comprising the peptide of SEQ ID NO: 10 and yRRRRRRRRRC comprising the peptide of SEQ ID NO: 16), a 1 niM stock solution in phosphate buffer/ dimethyl sulfoxide (DMSO) was prepared as described previously by Uhl et al. [27]. The required amount of radioactive iodine- 125 (¹²⁵I) was added to a 1: 1 mixture of 25 pL of the stock solution and 25 pL of a 0.25 M pH = 7.5 phosphate buffer. Labeling was performed using the chloramine T method according to Crim et al. (Crim et al., (2002), Peptides, 23(11), 2045-20 1). The reaction mixture was purified by preparative HPLC. Afterwards, the purity of the radiolabeled compound was determined by radio-HPLC (Agilent 1100 series) using a Chromolith^® Performance RP-18e, 100-3 mm column applying a linear gradient of 0.1% TEA in water (eluent A) to 0.1% TFA in acetonitrile (eluent B) within 5 min; flow rate 2 ml/min; UV absorbance l = 214 nm; g-detection. The procedures in this study were approved by the Animal Care and Use commitees at the

Regierungsprasidium Karlsruhe, Germany. Adult, female, Wistar rats (250 - 300 g) were purchased from Janvier Labs (Le Genest-Saint-Isle, France). The animals were anaesthetized by isoflurane inhalation and appropriate amounts of the ¹²⁵I labelled peptides, dissolved in 100 mΐ of

0.9% NaCl were injected into the tail vein. The scintigraphic images were obtained using a y- camera (Gamma Imager, Biospace, France). Cumulative images from 0-10 min, 60-70 min and 120-130 min after injection, were taken. For biodistribution studies, the animals were sacrificed after 1 h, the organs were removed and weighed and the radioactivity was measured using a Cobra Auto g-Counter, (Packard Bioscience, USA) in comparison with standards. The tissue-associated activity was related to the total inj ected dose (ID) and expressed as a percentage of the total inj ected dose per gram of tissue (%ID/g).

Example 13: Cytotoxicity

In order to exclude and to assess the extent of possible side effects of the antibiotics in future clinical application, its cytotoxic potency/activity towards human cells was assessed in a colorimetric viability assay. Suspended in culture medium, human PBMCs, HepG2 liver cells or HEK-293 kidney cells were seeded into 96-well microtiter plates (Costar^®, Coming, Tewksbury, MA, USA) at 2 x 10⁴ cells/well and cultured overnight (18-24 h) in a humidified atmosphere at 37 °C and 5% C0_2. The R6C conjugate and mitomycin c as control were added at final concentrations of 0.25 pg/mL up to 128 pg/mL in 2-fold dilution steps. Culture medium was carefully replaced after 24 h of incubation by 100 pL of fresh culture medium supplemented with 500 pg/mL of 3- (4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT; Sigma-Aldrich, Steinheim, Germany). After additional 3 h of incubation, formazan crystals were generated upon reduction of MTT by mitochondrial dehydrogenases within the remaining living cells. The precipitated purple- colored crystals were completely dissolved with 100 pL of dimethyl sulfoxide (DMSO; Sigma- Aldrich, Steinheim, Germany) upon thorough agitation. Adsorption was subsequently measured in an Infinite M200 PRO microplate reader (Tecan Trading, Maennedorf, Switzerland) at 570 nm.

Example 14: Structural analysis of FU002

0.17 mg FU002 were dissolved in 4 pi water and incubated in 100 pl TFA (trifluoroacetic acid) over night. TFA was removed in vacuum and the remaining substance was solved in water/ acetonitrile (1:1). Analytic was performed by HPLC-MS (see Fig. 16). Example 15: PET imaging of FU002

Radiolabeling of the compounds was performed according to the instructions of example 12, with the exception that the isotope ¹²⁴I was used. The animal trials were approved by the Animal Care and Use commitees at the Regienmgsprasidium Karlsruhe, Germany. Adult, female, Wistar rats (200 - 250 g) were purchased from Janvier Labs (Le Genest-Saint-Isle, France). The animals were anaesthetized by isoflurane inhalation and appropriate amounts of the ¹²⁴I-labelled peptides, dissolved in 100 mΐ of 0.9% NaCl were injected into the tail vein. PET-imaging was performed on an Inveon small animal PET scanner (Siemens). Therefore, the animals were sacrificed 10 min after injection of the radiolabeled compounds and images were taken immediately.

Example 16: MIC of the daptomycin conjugate FU004

The synthesis of daptomycin conjugates is performed analogous to the synthesis of the vancomycin conjugates disclosed herein. The minimal inhibitory concentration of daptomycin and a daptomycin-R6-Conjugate (FU004; see Fig. 26) on daptomycin sensitive (HG001 SA) and daptomycin-resistant bacteria (HG001 DRSA) was determined. No difference in MIC between daptomycin-sensitive (HG001 SA) and daptomycin-resistant bacteria (HG001 DRSA) is observed for FU004 (see Table 2). In contrast, the MIC of daptomycin itself is strongly increased on daptomycin resistant bacteria (HG001 DRSA) as expected. These results demonstrate the high benefit of FU004 with respect to daptomycin-resistant bacteria being able to overcome the daptomycin resistance.

Table 2:

* reported MIC: 31 pg/rnl (Muller et al., hit J Med Microbiol. 2018 Apr;308 (3) : 335-348)

Example 17: Biodistribution of daptomycin conjugate FU004 and daptomycin

The biodistribution of FU004 and daptomycin was determined at different time points (t = 10 min, 1 h, 2h and 3 h). The procedures in this study were approved by the Animal Care and Use committees at the Regienmgsprasidium Karlsruhe, Germany. Adult, female, Wistar rats (250 - 300 g) were purchased from Janvier Labs (Le Genest-Saint-Isle, France). The animals were anaesthetized by isoflurane inhalation and appropriate amounts of the ¹²⁵I labelled peptides, dissolved in 100 mΐ of 0.9% NaCl were injected into the tail vein. The scintigraphic images were obtained using a g-camera (Gamma Imager, Biospace, France). Cumulative images from 0-10 min. 60-70 min and 120-130 min after injection, were taken. For biodistribution studies, the animals were sacrificed after 1 h, the organs were removed and weighed and the radioactivity was measured using a Cobra Auto g-Counter, (Packard Bioscience, USA) in comparison with standards. The tissue-associated activity was related to the total injected dose (ID) and expressed as a percentage of the total injected dose per gram of tissue (%ID/g).

FU004 accumulates predominantly in the liver (Fig. 27; Ih) and shows elimination via the intestines and kidneys starting 1 h post administration. Daptomycin accumulates in the kidneys (Fig. 28) and shows an elimination starting 1 h post administration.

Example 18: In vivo toxicity of conjugate FU002 and vancomycin The in vivo toxicity of FU002 and vancomycin was determined in CD-I female mice. The study included three treatment groups: (1): 0.9% NaCl (10 ml//kg; iv); (2) vancomycin (30 mg/kg; iv) and (3) vancomycin conjugate FU002 (56.4 mg/kg; iv). Respective treatment was applied twice daily for the first 5 days. Total duration was 14 days.

Body weight development of the mice was recorded on days 0, 3, 7, 10 and 14 (see figure 28). On day 14 the animals were sacrificed and liver and kidney samples were assessed histologically. No treatment related findings due to the treatment with vancomycin or vancomycin conjugate (FU002) were observable in the liver or kidney.

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Biopharmaceutics 103 (2016): 159-166. Items

The following items represent preferred embodiments of the present invention.

1. An antibiotic comprising an antibiotic core and at least one polypeptide of a length of 2 to 20 amino acids, preferably of a length of 2 to 12 amino acids, wherein the N-terminus of the polypeptide is not attached to a lipophilic group and the polypeptide is positively charged and optionally a linker connecting the antibiotic core and the polypeptide, wherein the antibiotic core is selected from the group consisting of a glycopeptide antibiotic; a cyclic lipopeptide antibiotic; a B-lactam antibiotic, a cephalosporine antibiotic; and an oxazolidinone antibiotic; preferably a glycopeptide antibiotic and a cyclic lipopeptide antibiotic.

2. The antibiotic of item 1, wherein the:

(i) glycopeptide antibiotic is selected from the group consisting of vancomycin, teicoplanin, A477, A35512, A40926, A41030, A42867, A47934, A80407, A82846, A83850, A84575, AB-65, actaplanin, actinoidin, ardacin, avoparcin, azureomycin, balhimycin, chloroorientiein, chloropolysporin, dalbavancin, decaplanin, N- demethylvancomycin, eremomycin, galacardin, helvecardin, izupeptin, kibdelin, LL- AM374, mannopeptin, MM45289, MM47756, MM47761, MM49721, MM47766, MM55260, MM55266, MM55270, MM56597, MM56598, OA-7653, orenticin, parvodicin, ristocetin, ristomycin, symnonicin, telavancin, UK-68597, UK-69542, and UK-7205 or antibiotic structural analogs thereof;

(ii) cyclic lipopeptide antibiotic is selected from the group consisting of daptomycin dalbavancin, oritavancin and telavancin;

(iv) cephalosprine antibiotic is selected from the group consisting of cefazolin, cefadroxil, cephalexin, cefuroxim, cefotiam, cefaclor, cefuroxim, loracarbef, cefixim, cefpodoxim, ceftibuten, cefotaxim, ceftriaxon, ceftazidim, cefepim ceftobiprol, ceftolozan, ceftarolin; and

(v) oxazolidinone antibiotic is linezolid.

3. An antibiotic of one of the structures (I) or (II)

wherein:

L is a linker;

X_j is selected from: -OH, -(NH)_r-(CH₂)_s-N-(CH₂)₂, -(NH)-(CH₂)_U-(NH)-P_p, -(NH)-(CH₂)_U- (NH)-L-Pp, -P_P or -L-Pp, -(C=0)-(CH₂)_t-CH₃

X₂ is selected from structure (

wherein Y_t is selected from -H, -OH, and -NH-Y₉,

wherein Y₉ is selected from -H, -(C¾)_¥-NH₂, -(CH₂)_V-NH-(CH₂)_W-CH₃, -(C=0)- (CH₂)_t-CH₃, -(CH₂)_q-chlorobiphenyl, chlorobiphenyl, -(CH₂)_U-(NH)-P_P, -(CH₂)_U- (NH)-L-P_P, -P_p and -L-P_p, wherein u is an integer ranging from 1 to 4, preferably 2 to 3, q is an integer ranging from 1 to 4, preferably 1 to 2, v is an integer ranging from 1 to 4, w is an integer ranging from 6 to 12, t is an integer ranging from 2 to 18, preferably 4 to 16, P_p is said polypeptide and L is said linker,

wherein Y₂ is selected from -H and -C¾,

wherein Y₆ is selected from -H, and -0-Y₈,

wherein Y₈ is a substituted tetrahydrofuranyl, preferably a substituted tetrahydrofuranyl-3-4-diol, more preferably 2-(hydroxymethyl)tetrahydrofuranyl-3-3- diol,

wherein Y₃ is (i) a branched or unbranched C₈ to C₁₂ alkyl or alkenyl, preferably a C₉ alkenyl or a C_n alkyl, or;

(ii) a branched or unbranched C₃ to C_l9 alkyl or alkenyl, preferably a branched or unbranched C₅ to C₁₇ alkyl or alkenyl, more preferably a C₅ to Ci7 alkyl, most preferably a C₉ to Cn alkyl.

X₃ is selected from -NX_I4-CH₃ and -NH-Xn,

wherein Xi₄ is selected from -H, -P_P and -L-P_P, -(CH₂)_U-(NH)-Pp, -(CH₂)_u-(NH)-L-Pp, -(C=0)-(CH₂)_t-CH₃, wherein t is an integer ranging from 4 to 16, u is an integer ranging from 1 to 4, preferably 2 to 3,

wherein X₁₅ is selected from -H, -P_p and -L-P_p, -(CH )_U-(NH)-P_p, -(CH₂)_U-(NH)-L-P_P, -(C=0)-(CH₂)_t-CH₃ wherein t is an integer ranging from 2 to 18, preferably 4 to 16, u is an integer ranging from 1 to 4, preferably 2 to 3;

X4 is selected from -H, -(CH₂)_n-NH -(CH₂)_n -P_P -(CH₂)_n-NH-(CH₂)^-L-P_P; -(CH₂)_n-NH- P_p, -(CH₂)_n-NH-L-P_P -P_p, -L-P_p and a substituted phosphonic acid, preferably substituted methylamino-phosphonic acid, wherein n is an integer ranging from 1 to 4, preferably 2 to 3, wherein n’ is an integer ranging from 1 to 4, preferably 2 to 3;

X₅ is selected from -H, and substituted tetrahydropyranyl, preferably amino-methyl- hydroxy-tetrahydropyranyl or (dihydroxy-hy dr oxymethy l-tetrahydropyran)-acetamide ; C_b is selected from -H, -Cl, -F, -Br, and -I;

X₇ is selected from -H, -Cl, -F, -Br, and -I;

X₈ is selected from -H and -O-Y ₁₀,

X9 is selected from -H and substituted tetrahydropyranyl, preferably hydroxymethyl— friliydroxy-tetrahydropyranyl or (methylacetate)-trihydroxytetrahydro-pyranyl;

X10 is selected from acetamide and substituted or unsubstituted phenyl, preferably phenyl or halobenzyl, and X_n is selected from C₃ to C₆ alkyl, preferably a C alkyl, substituted phenyl, preferably methyl-trihydroxy-tetrahydropyranyl substituted phenyl; or

X₁₀ and X_u are linked by a unsubstituted or substituted diphenyl ether, preferably a substituted or unsubstituted hydroxyphenoxy-phenyl, more preferably hydroxyphenoxy-phenyl, halo-hydroxyphenoxy-phenyl or methyl-hydroxyphenoxy- phenyl;

X₁₂ is selected from -CH₂-OH, -COOH, -0-Y_n ,

wherein Y_n is substituted tetrahydropyranyl, preferably methyltrihydroxytetrahydropyranyl,

wherein the antibiotic of (I) comprises at least one P_p;

or

wherein Wi is selected from -P_p or -L-P_p. The antibiotic according to item 3, wherein the positively charged polypeptide (P_p) or the linker forms a bond to

(i) the indicated residues of structure (I):

wherein:

Xi is selected from -OH,

, -(NH)-(CH₂)_U-(NH)-P_p, -(NH)-(CH₂)_U-(NH)-L-P_p, -P_P or -L-P_p, wherein u is an integer ranging from 1 to 4, preferably 2 to 3, wherein P_p is said polypeptide and L is said linker, with the proviso that the N-terminus of P_p is preferably not attached to a lipophilic group;

X₂ is selected from structure (PI), or -NH-CO-Y₃,

wherein Y₃ is selected from -H, -OH,

wherein Y₂ is -H, -C¾,

wherein Y₃ is (i) a branched or unbranched C₈ to C₁₂ alkyl or alkenyl, preferably a C₉ alkenyl oraC_n alkyl; or (ii) a branched or unbranched C₃ to C₁₉ alkyl or alkenyl, preferably a branched or unbranched C₅ to C₁₇ alkyl or alkenyl, more preferably a C₅ to C_|7 alkyl, most preferably a C₉ to Cy alkyl.

wherein Y₆ is selected from -H or

X₃ is selected from -NX_I4-C¾ or -NH-X₁₅,

wherein X₁₄ is selected from -H, -P_p or -L-P_p, -(CH₂)_U-(NH)-P_p, -(C¾)_U-(NH)-L-

P_p, wherein 11 is an integer ranging from 1 to 4, preferably 2 to 3, wherein P_p is said polypeptide and L is said linker,

wherein X₁₅ is selected from -H, -P_p or -L-P_p, -(CH₂)_U-(NH)-P_p, -(CH₂)_U-(NH)-L-

P_p, wherein u is an integer ranging from 1 to 4, preferably 2 to 3, wherein P_p is said polypeptide and L is said linker; X₄ is selected from -H, -P or -L-Pp, wherein P_P is said polypeptide and L is said linker:

X₅ is selected from

g is selected from -H, -Cl;

X₇ is selected from -H, -Cl;

Xs is selected from -OH, -H, or

X₉ is selected from -H or , wherein Y₇ is selected from -H or-CO-C¾;

X₁₀ is selected from , wherein Y₅ is selected from -H or -Cl, and X_n is selected from C₃ to C₆ alkyl, preferably a C₄ alkyl,

or

Xio and Xu are linked by whereby Y₄ is selected from

-H, -CH₃, or -Cl;

X12 is selected from -C¾-OH, -COOH or The antibiotic of any one of items 3 and 4, wherein the positively charged polypeptide comprises 2 to 30, preferably 2 to 15, lysine and/or arginine residues. The antibiotic of any one of items 1 to 2, wherein the polypeptide or the l inker forms a bond to

(i) the indicated residues of structure (I):

wherein:

Xx is selected from: -OH, -(NH)_r-(CH₂)_s-N-(CH₂)₂, -(NH)-(CH₂)_U-(NH)-P_p, -(NH)- (CH₂)_U-(NH)-L-P_P , -P_P or -L-P_P, -(C=0)-(CH₂)_t-CH₃,

wherein u is an integer ranging from 1 to 4, preferably 2 to 3, r is selected from 0 or 1, s is an integer ranging from 1 to 6, preferably 2 to 4, more preferably 3 to 4, t is an integer ranging from 4 to 16, wherein P_p is said polypeptide and L is said linker, with the provisio that the N- terminus of P_p is preferably not attached to a lipophilic group;

X₂ is selected from structure (PI), or -NH-CO-Y₃,

wherein Y 1 is selected from -H, -OH, -NH-Y_¾

wherein Y₉ is selected from -(CH^-NH-CCH^-CHs, -(C=0)-(CH₂)_t-CH₃, - (CH₂)_q-chlorobiphenyl, chlorobiphenyl, -(CH₂)_U-(NH)-P_p, -(CH₂X_J-(NH)-L-P_P ,-Pp or -L-Pp, wherein q is an integer ranging from 1 to 4, preferably 1 to 2, u is an integer ranging from 1 to 4, preferably 2 to 3, t is an integer ranging from 4 to 16, v is an integer ranging from 1 to 4, w is an integer ranging from 6 to 12, P_p is said polypeptide and L is said linker,

wherein Y₂ is -H or -€¾,

wherein Y₆ is selected from -H, -0-Y₈,

wherein Y₈ is a substituted tetrahydrofiiranyl, preferably a substituted tetrahydrofuranyl-3-4-diol, more preferably 2-

(hydroxymethyl)tetrahydrofuranyl-3-3-diol,

wherein Y₃ is (i) a branched or unbranched C₈ to C₁₂ alkyl or alkenyl, preferably a

C₉ alkenyl or a C_u alkyl; or

(ii) a branched or unbranched C₃ to C₁₉ alkyl or alkenyl, preferably a branched or unbranched C₅ to C₁₇ alkyl or alkenyl, more preferably a C₅ to C₁₇ alkyl, most preferably a C₉ to Cu alkyl;

X₃ is selected from -NX₁₄-CH₃ or -NH-X₁₅,

wherein X_l4 is selected from -H, -P_P or -L-P_P, -(CH₂)_U-(NH)-P_P, -(C¾)_U-(NH)-L- P_p, -(C=0)-(CH₂)_t-CH₃, wherein t is an integer ranging from 4 to 16, u is an integer ranging from 1 to 4, preferably 2 to 3; wherein P_P is said polypeptide and L is said linker

wherein X₁₅ is selected from -H, -P_p or -L-P_p, -(CH )_U-(NH)-P_p, -(CH₂)_U-(NH)-L- P_p, -(C=0)-(CH₂)_t-CH₃, wherein t is an integer ranging from 4 to 16, 11 is an integer ranging from 1 to 4, preferably 2 to 3, wherein P_p is said polypeptide and L is said linker;

X_{4 i}s selected from -H, -{CH₂)_n-NH -(C¾V-P_P -(CH₂)_n-NH-(CH₂)_n.-L-P_P; -(CH₂)_n- NH-P_P, -(CH₂)_n-NH-L-Pp -P_p, -L-P_p or a substituted phosphonic acid, preferably substituted methylamino-phosphonic acid, herein n is an integer ranging from 1 to 4, preferably 2 to 3, wherein o’ is an integer ranging from 1 to 4, preferably 2 to 3; wherein P_P is said polypeptide and L is said linker; X₅ is selected from -H, or substituted tetrabydropyranyl, preferably amino-methyl- hydroxy-tetrahydropyranyl or (dihydroxy-hydroxymethyl-tetrahydropyran)- acetamide;

¾ is selected from -H, -Cl, -F, -Br, -I;

X₇ is selected from -H, -Cl, -F, -Br, -I;

X₈ is selected from -H or -O-Y ₁₀,

wherein Y₁₀ is selected from -H or substituted tetrabydropyranyl, preferably hydroxymethyl-trihydroxy-tetrahydropyranyl;

X₉ is selected from -H or substituted tetrahydropyranyl, preferably hydroxymethyl— trihydroxy-tetrahydropyranyl or (methylacetate)-trihydroxytetrahydro-pyranyl;

X₁₀ is selected from acetamide or substituted or unsubstituted phenyl, preferably phenyl orhalobenzyl, and Xu is selected from C₃ to C₆ alkyl, preferably a C₄ alkyl, substituted phenyl, preferably methyl-trihydroxy-tetrahydropyranyl substituted phenyl; or

X₁₀ and X_u are linked by a substituted phenyl ether, preferably a substituted or unsubstituted hydroxyphenoxy-phenyl, more preferably hydroxyphenoxy-phenyl, halo-hydroxyphenoxy-phenyl or methyl-hydroxyphenoxy-phenyl;

X₁₂ is selected from -C¾-OH, -COOH, -0-U_p ,

wherein Y_u is substituted tetrahydropyranyl, preferably methyltrihydroxytetrahydropyranyl,

(ii) the indicated residues of structure (P):

wherein Wi is selected from -P_P or -L-P_P, wherein P_P is said polypeptide and L is said linker.

7. The antibiotic of any of items 1 to 6, wherein the linker or the polypeptide is conjugated to:

(i) a primary or secondary amine of the antibiotic core, preferably forming a peptide bond between antibiotic and the linker or the polypeptide;

(ii) a carboxy group of the antibiotic core, preferably forming a peptide bond or an ester bond between the antibiotic and the linker or the polypeptide;

(iii) a hydroxyl group of the antibiotic core, preferably forming an ester bond or ether bond between the antibiotic and the linker or the polypeptide.

8. The antibiotic of any one of items 1 to 7, wherein the polypeptide is linear or circular and:

(i) has a length of between 3 and 15 amino acids, preferably a length of between 3 to 12 amino acids; and/or (ii) comprises at least 3, preferably at least 4, at least 5 or at least 6 arginine residues; and/or

(iii) comprises or consists of the following amino acid sequence: RRRRRR (SEQ ID NO:

1); RRRRR (SEQ ED NO: 2), RRRR (SEQ ID NO: 3), RRR, RRRRRRR (SEQ ID NO: 4), RRRRRRRR (SEQ ID NO: 5), RRRRRRRRR (SEQ ED NO: 6), RRRRRRRRRR (SEQ ID NO 7), RRRRRRRRRRR (SEQ ID NO: 8), RRRRRRRRRRRR (SEQ ID NO: 9), RRRRRRC (SEQ ID NO: 10); RRRRRC (SEQ ID NO: 11), RRRRC (SEQ ID NO: 12); RRRC (SEQ ID NO: 13), RRRRRRRC (SEQ ID NO: 14), RRRRRRRRC (SEQ ID NO: 15), RRRRRRRRRC (SEQ ID NO: 16), RRRRRRRRRRC (SEQ ID NO 17), RRRRRRRRRRRC (SEQ ID NO: 18), RRRRRRRRRRRRC (SEQ ED NO: 19); RRK, RKR, RKK, KRK, KKR, RRRK (SEQ ID NO: 20), RRKR (SEQ ID NO: 21), RKRR (SEQ ID NO: 22), KRRR (SEQ ID NO: 23), RRKK (SEQ ED NO: 24), RKRK (SEQ ID NO: 25), KRKR (SEQ ID NO: 26), RKKR (SEQ ED NO: 27), KKRR (SEQ ID NO: 28), KRRK (SEQ ED NO: 29), KKKR (SEQ ID NO: 30), KKRK (SEQ ID NO: 31), KRKK (SEQ ED NO: 32), RKKK (SEQ ID NO: 33), KKKK (SEQ ED NO: 34), RRRKK (SEQ ID NO: 35), RRRKKK (SEQ ED NO: 36), CRRR (SEQ ID NO: 37), CRRRR (SEQ ED NO: 38); CRRRRR (SEQ ED NO: 39), CRRRRRR (SEQ ID NO: 40); CRRRRRRR (SEQ ID NO: 41), CRRRRRRRR (SEQ ID NO: 42), CRRRRRRRRR (SEQ ID NO: 43), CRRRRRRRRRR (SEQ ID NO: 44), CRRRRRRRRRRR (SEQ ED NO: 45), CRRRRRRRRRRRR (SEQ ID NO: 46), KKKKKKC (SEQ ID NO: 47), RRRKKKC (SEQ ID NO: 48), RRRKKKC (SEQ ID NO 49), WWWRRRC (SEQ ID NO: 50), RRRGPRRRC (SEQ ID NO: 51), WRRLRRRVRC (SEQ ID NO: 52), RRWWRWWC (SEQ ID NO: 53), KRWWKWWC (SEQ ED NO: 54), CYRRRRRR (SEQ ID NO: 55) and CRRRRRRY (SEQ ID NO: 56) optionally wherein the carbonyl- group of C -terminal cysteines is substituted by a carboxamide group and/or

(iv) additionally, comprises one or more amino acids selected from the group consisting of Dab, C, A, G, or K; and/or

9. The antibiotic of any one of items 1 to 8, wherein the antibiotic core or the linker is coupled to the N- or C-terminus of the polypeptide or to the side chain of an amino acid of the polypeptide.

10. The antibiotic of any one of items 1 to 9, wherein the optional linker when present is selected from the group consisting of: -O(CR₂₀R₂₁)_ni(CR₂₂R₂₃)_n(OCH₂CH₂)_p(C _{40 4i})_P'-Y"(CR₂₄R₂₅)_t!(C=O)₁X"

-0(CR₂₀R₂₁)_m(CR₂₂R₂₃)_I1(OCH₂CH₂)_p(CR₄oR_4i)_p.-Y"(CR₂₄R₂₅)_q(NH)_tX",

-0(CR₂oR2i)_m(CR₂₂R₂₃)_n(OCH₂CH₂)p(€R4oR4i)_P ^»Y"(CR₂₄R₂₅)qX"

-0(CR₂oR₂₁)_ni(CR₂₆=CR₂₇)_m<CR₂₂R₂₃)_n(OCH₂CH₂)_p(CR₄oR_4i)_P»Y"(CR₂₄R₂₅)_q(C=0)_tX",

-O(CR₂₀R₂₁)_m(CR₂₆=CR₂₇)_m<CR₂₂R₂₃)_n(OCH₂CH₂)_p(CR₄₀R₄₁)_p-Y"(CR₂₄R₂₅)_£1(NH)_tX'',

-0(CR₂oR₂₁)_m(CR_2(j=CR₂₇)_m-(CR₂₂R₂₃)_n(OCH₂CH₂)_p(CR₄oR₄₁)_p"Y^,,(CR₂₄R₂₅)_qX",

-O(CR₂₀R₂₁)_ni(alkyiiyl)₁₁<CR₂₂R₂3MOCH₂CH₂)_p(CR₄₀R₄₁)_p.Y"(CR₂₄R₂₅)_q(C=O)_tX",

-0(CR₂oR_2i)_m(alkyiiyl)_I1<CR₂₂R₂₃)₁₁(OCH₂CH₂)_p(CR₄oR_4i)_P»Y"(CR₂₄R₂₅)_q(NH)_tX",

-0(CR₂oR₂₁)₁₁₁(alkyiiyl)₁₁<CR₂₂R₂3)_I1(OCH₂CH₂)_p(CR₄₀R₄₁)_p.Y^w(CR24R₂5)_qX",

-O(CR₂₀R₂₁)_m(piperazino)_t<CR₂₂R₂₃)_I1(OCH₂CH₂)_p(CR₄₍₎R₄₁)_p»Y"(CR₂4R₂5)_q(C=O)_tX",

-O(CR₂₀R₂₁)_m(piperaziiio)_t CR₂₂R₂₃)_I1(OCH₂CH₂)_p(CR_4{)R₄₁)_p»Y"(CR₂₄R₂₅)_q(NH)_tX"

-0(CR₂oR₂₁)_m(piperaziiio)t-(CR2₂R₂₃):_a(OCH₂CH₂)_p(CR4oR4i)p^»Y"(CR₂₄R25)_qX"

-O(CR₂₀R₂₁)_m(pynOloMCR₂₂R₂₃)_n(OCH₂CH₂)_p(CR₄₀R_4i)_pY''(CR₂₄R₂₅)_q(C=O)_tX",

-0(CR₂₀R₂₁)_m(pyiToloHCR₂₂R₂₃)_n(OCH₂CH₂)_p(CR₄oR_4i)_pY"(CR₂₄R₂₅)_q(NH)_tX",

-0(CR₂o _2i)_m(p iTolo)_t'(C _{22 23})_n(OCH₂CH )_p(C ₄o _4i)_p.¾ "(CR₂₄R₂₅)_qX”,

-0(CR₂₀R₂₁)_niA"_m«{CR₂₂R₂₃)_I1(OCH₂CH₂)_p(CR₄oR_4i)_p'-Y"(CR₂₄R₂₅)_q(C=0)_tX",

-S(CR₂₀R₂₁)_m(CR₂₂R₂₃)_n(OCH₂CH₂)_p{CR₄oR₄₁)_p»Y"(CR₂₄R₂₅)₁X",

-S(CR₂₀R₂₁)_m(CR₂₆=CR₂₇)_m<CR₂₂R₂₃)_I1(OCH₂CH₂)_p(CR₄₀R_4i)_p'Y"(CR₂₄R₂₅)_q(C=O)_tX",

-S(CR₂oR_2i)_m(CR₂₆=CR₂₇)_m<CR₂₂R₂₃)_n(OCH₂CH₂)_p(CR₄₀R_4i)_P»Y"(CR₂₄R₂₅)_q(NH)_tX",

-S(CR₂₀R₂₁)_m(CR₂₆=CR₂₇)_m<CR₂₂R₂₃)_I1(OCH₂CH₂)_p(CR₄₀R4i)_P-Y"(CR24R25)qX",

-S(CR₂₀R₂₁)_m(alkyiiyl)_I1<CR₂₂R₂3)_n(OCH₂CH₂)_p(CR₄₀R₄₁)_P-Y"(CR₂₄R₂₅)_q(C₃=0)_tX",

-S(CR₂₀R₂₁)_ni(alkyiiyl)_n,(CR₂₂R₂3)_n(OCH₂CH₂)_p(CR₄₀R₄₁)_P-Y"(CR₂₄R₂₅)_q(NH)_tX",

-S(CR₂₀R₂₁)_m(alkyiiyl)_I1<CR₂₂R₂3)_n(OCH₂CH₂)_p(CR₄₀R₄₁)_p.Y^,'(CR₂₄R₂₅)_qX"

-S(CR₂₀R₂₁)_m(pip€^:raziiio)_t<CR₂₂R₂₃)_I1(OCH₂CH₂)_p(CR₄oR_4i)_P-Y"(CR₂₄R₂₅)_q(C=0)tX",

-S(CR₂₀R₂₁)_ni(|jip€raziiio)_t'{CR₂2R₂₃)_n(OCH₂CH₂)_p(CR₄₀R₄₁)_p-Y"(CR₂₄R₂₅)_q(NH)_tX",

-S(CR₂₀R₂₁)_m(pipera.ziiio)_f(CR₂₂R₂3)_n(OCH₂CH₂)_p(CR₄₀R4₁)_p-Y (CR₂₄R₂₅)_qX",

-S(CR₂₀R₂₁)_m(p}iTolo)_t-(CR₂₂R₂₃)_n(OCH₂CH₂)_p(CR₄₀R₄₁)_p-,Y"(CR₂₄R₂₅)_q(C=0)_tX",

-S(CR₂₀R_2i)_m(pyiTolo)_t.(CR₂₂R₂₃)₁₁(OCH₂CH₂)_p(CR₄₀R_4i)_p-Y"(CR₂₄R₂₅)_q(NH)_tX",

-S(CR₂₀R2i)_ni(pyrrolo)t<CR2₂R₂₃)_D(OCH₂CH₂)_p(CR4oR4i)_P ^»Y"(CR₂₄R₂₅)c_!X",

-S(CR₂₀R_2i)_I11A"_m-(CR₂₂R₂₃)_n{OCH₂CH₂)_p(CR₄oR_4i)_P»Y''(CR₂₄R₂₅)_q(C=0)_tX"

-S(CR₂₀R_2i)_mA"_m CR₂₂R₂₃)_n(OCH₂CH₂)_p(CR₄₀R_4iVY"(CR₂₄R₂₅)_q(NH)_tX", -S(CR₂₀R₂₁)_nA"_m"(CR₂₂R₂₃)_n(OCH₂CH₂)_p(CR₄₀R₄₁)_P»Y"(CR₂₄R₂₅)_[IX",

-NR₃₃(C=O)_p.<CR₂₀R₂₁)_m(CR₂₂R₂₃)_n(OCH₂CH₂)_p(CR₄₀R₄₁)_p.Y"(CR₂₄R₂₅)_q(C=O)_tX",

-NR₃₃{C=0)_p CR₂oR_2i)_m(CR₂₂R₂₃)_I1(OCH₂CH₂)_p(CR₄₀R_4i)_p-Y"(CR₂₄R₂₅)_q(NH),X"₃

-NR₃₃(C=0)_p CR₂oR2i)_m(CR₂₂R₂₃)_n(OCH₂CH₂)_p(CR₄oR4i)_P'Y"(CR24R25)₁X",

-NR₃₃(C=O)_p CR₂₀R₂₁)_m(CR₂₆=CR₂₇)_m<CR₂₂R₂₃ OCH₂CH₂)_p(CR_4{)R₄₁)_p.Y"(CR₂₄R₂₅)_q-

(C=0)_tX",

-NR₃₃(C=O)_p CR₂₀R₂₁)_m(CR₂₆=CR₂₇)_m<CR₂₂R₂₃ OCH₂CH₂)_p(CR₄₀R4₁)_p.Y"(CR24R₂₅)_q-

(NH)_tX",

-NR₃₃(C=O)_p CR₂₀R₂₁)_m(CR₂₆=CR₂₇)_ni<CR₂₂R₂₃ OCH₂CH₂)_p(CR₄₀R₄₁)_p»Y"(CR₂₄R₂₅)₍₁-

X",

-NR₃₃(C=O)_p»(CR₂₀R₂₁)_m(alkjT;iyl)_:a-(CR₂₂R₂₃) ₁(OCH₂CH₂)_p(CR4₀R ₁)_p»Y"(CR₂4R₂5)_q-

(C=0),X",

-NR₃₃(C=0)_p-<CR₂₀R₂₁)_m(alkyiiyl)_:a CR₂₂R₂₃)_n(OCH₂CH₂)_p(CR₄oR_4i)_P-Y"(CR₂₄R₂₅)_q-

(NH)_tX",

-NR₃₃(C=0)_p CR₂₀R₂₁)_m(alkyiiyl)_n<CR₂₂R₂₃)_n(OCH₂CH₂)_p(CR₄oR_4i)_p-Y"(CR₂₄R₂₅)_qX'',

-NR₃₃(C=O)_p,<CR₂₀R₂₁)_m(l3iperazmoMCR₂₂R₂₃)_n(OCH₂CH₂)_p{CR₄₀R₄₁)_P"Y"(CR₂₄R₂₅)_q-

(c=o x

-NR₃₃ (C=0)_p-. (CR₂₀R_2i)_m(pip erazmo)_t<(CR₂₂R₂3)_n(OC H₂C H₂)_p(C ₄₀R_4l)_p> Y" (CR₂₄R₂5)_q- (NH)_tX",

-NR₃₃ (C=0)_p« (CR₂₀R_2i)_m(pip erazmo)_f(CR₂₂R₂3)_n(OC H₂CH₂)_p(C R4oR4i)_p"Y" (CR_{24 2}5)_qX " , -NR₃3(C=O)_p-<CR₂₀R₂₁)_ni(pynOlo)r(CR₂₂R₂3)_n{OCH₂CH₂)_p(CR₄₀R₄₁)_P™Y"{CR₂₄R₂₅)_q~ -

(OO X",

-NR₃₃(C=O)_p-<CR_2{,R₂₁)_m(pynOlo)_t<CR₂₂R₂₃)_n{OCH₂CH₂)_p(CR₄₀R_4i)_p'Y"(CR₂₄R₂₅)_q—

(NH)_tX",

-NR₃₃ (C=0)_p« (CR_2QR_{2 i})_m(pyiTolo)_f (CR₂ R₂₃)_n(OC H₂C H₂)_p(C R₄oR_4i)_p''Y” (C _{24 25})_q , cycloalkyl)_f{CR₂₂R₂₃)_n(2,5- yl)_t'(C ₂₂R₂₃)_n(2 , 5 - dioxopyiTolIdiiiyl)_p(CR₂₄R₂₅)_p.-(NH)_t X" ,

-NR₃₃(C=0)_p«(CR_2{)R₂₁)_m(C₄-C₇-cycloalkyl)_t'(CR₂₂R₂₃)_n(2,5- dioxopynolidmyl)_p(CR₂₄R₂₅)_p»X",

-NR₃₃(C=O)_p CR₂₀R₂₁)_mA"_n,'<CR₂₂R₂₃)_n(OCH₂CH₂)_p(CR40R4i)_P"Y"(CR₂₄R₂₅)q(C=O)tX"_!

-NR₃₃(C=O)_p CR₂₀R₂₁)_mA"_m.<CR₂₂R₂₃)_n{OCH₂CH₂)_p(CR₄₀R_4i)_p»Y"(CR₂₄R₂₅)_q(NH)_tX",

-NR₃₃(C=O)_p.<CR₂₀R₂₁)_mA"_ni ^»(CR₂₂R₂₃)_n(OCH₂CH₂)_p(CR4₀R4i)_P ^»Y"(CR₂₄R₂₅)qX"₃ -(C=O)_p.(CR₂₀R₂₁)_m(CR₂₂R₂₃)_nCOCH₂CH₂)_p(CR₄₀R₄₁)_p»Y"(CR₂₄R₂₅)_q(NH)_tX",

-(C=O)_p»(CR₂₀R₂₁)_m(CR₂₂R₂₃)_a(OCH₂CH₂)_p(CR₄₀R₄₁)_P'-Y"(CR₂₄R₂₅)_qX''

-(C=0)_p CR₂₀R_2i)_ai(CR₂₆= R₂₇)_J1,(CR₂₂R₂₃)_n(OCH₂CH₂)_p(CR₄oR_4i)_p»Y"(CR₂₄R₂₅)_q-

(C=0)_fX",

-(C=O)_p«(CR₂₀R₂₁)_m(pyiTolo)_|.(CR₂₂R₂₃)_n(OCH₂CH₂)_p(CR₄₀R₄₁)_p«Y"(CR₂₄R₂5)_tl— (NH)_tX", -(C=O)_p»{CR₂₀R₂₁)_m(pynOlo)_r(CR₂₂R₂₃)_n(OCH₂CH₂)_p(CR₄₀R₄₁)_p»Y"(CR₂₄R₂₅)_tlX''

- (C=0)_p»(C R₂₀R_{2 i})_m{C₄-C₇-cycloalkyl)_f (CR₂₂R₂₃)_n(2, 5 - dioxopyiTolidiiiyl)_p(CR₂₄R₂₅)_p"(C=0)_tX",

-(C=0)_p»(CR₂oR_2i)_m(C₄-C₇-cycloalkyl)r(CR₂₂R₂₃)_n(2,5- dioxopyrrolidmyl)p(CR24R₂₅ VCNH ^x” ,

-(C=0)_p,{CR₂oR_{2 i})_m(C₄-C₇-cycloalkyl)_r(CR₂₂R₂₃) (2, 5 -dioxopynOlidinyl)_p(CR₂₄R₂₅)_p»X" ,

.(C-O)_p»(CR₂₀R₂₁)_mA"_m-<CR₂₂R₂₃)₁₁(OCH₂CH₂)_p(CR₄₀R₄₁)_p»Y"(CR₂₄R₂₅) ₁(C=O)_tX",

-(CR₂₀R₂₁)_m(CR₂₆=CR₂₇)_m<CR₂₂R₂₃)_n(OCH₂CH₂)_p(CR₄oR_4i)_P»Y"(CR₂₄R₂₅)_q(C=0)_tX",

-(CR₂oR₂₁)_m(CR₂₆=CR₂₇)_m'(CR₂₂R₂₃)_n(OCH₂CH₂)_p(CR₄oR_4i)_p'Y"(CR₂₄R₂₅)_q(NH)_tX",

-(CR₂oR₂₁)_m(CR₂₆=CR₂₇)_m<CR₂₂R₂₃MOCH₂CH₂)p(CR4oR4i)_P™Y"(CR24R₂₅)_tlX"

-(CR₂oR₂₁)_ni(alL_Tiiyl)_n.{CR₂₂R₂₃)_:n(OCH₂CH₂)_p(CR₄₀R₄₁)_p-Y"(CR₂₄R₂₅)_q(C=0)_tX" -(CR₂₀R₂₁)_ni(alLTiiyl)₁₁<CR₂₂R₂3)_n(OCH₂CH₂)_p(CR₄₀R₄₁)_p»Y"(CR₂₄R₂₅)_q(NH)_tX",

-(CR₂₀R₂₁)_m(aliwlWCR₂₂R₂₃)_n(OCH₂CH₂)_p(CR₄₀R₄₁)_p»Y '(CR₂₄R₂₅)_qX",

-(C ₂o _2i)_ni(piperaziiio)_t'(C _{22 23})_n(OCH₂CH₂)_p(C ₄oR_4i)_P' "(CR₂₄R₂₅)_q(C=0)_tX",

-(CR₂₀R₂₁)_m(piperaziiio)t<CR₂₂R₂₃MOCH₂CH₂)p(CR4₀R4i)_p ^»Y"(CR₂₄R₂₅)_q(NH)tX",

-(CR₂₀R₂₁)_m piperaznio)_t<CR₂₂R₂₃)_nCOCH₂CH₂)_p(CR₄₍₎R₄₁)p^»Y"(CR24R₂₅)_qX",

-(CR₂oR₂₁)_mA"_m*(CR₂₂R₂₃)_I1(OCH₂CH₂)_p(CR₄oR₄₁)_p»Y"(CR₂₄R₂₅)_q(C=0)_tX",

-(CR₂₀R₂₁)_mA"_m-(CR₂₂R₂₃)_n(OCH₂CH₂)_p(CR₄₀R₄₁)_p»Y"(CR₂₄R₂₅)_q(NH)_tX"

C=0)_tX",

-(CR₂₀R₂₁)_m(CR₂₉N-NR₃₀)₁₁<alkynyl)_I1<CR₂₂R₂₃)_I1(OCH₂CH₂)_p{CR4oR4i)_P-Y"(CR₂4R₂₅)

(NH)_tX",

-(CR₂oR₂₁)_m(CR₂₉N-NR₃₀)_n-(alkynyl)_rf(CR₂₂R₂₃)_n(OCH₂CH₂)p(CR₄oR_4i)p_"Y"(^cR2₄R₂₅)q-X'',

-(CR₂₀R₂₁)_m(CR₂^=N-NR₃₀)_tfA"_m ^»(CR₂₂R₂₃)_I1(OCH₂CH₂)_p(CR4₀R4i)_P-Y"(CR₂₄R25)q-

(C=0)_tX",

-(CR₂₀R₂₁)_m(CR_2i =N-NR₃o)_n-A"_m CR₂₂R₂₃)_n(OCH₂CH₂)_p(CR4oR4i)_P ^«Y"(CR₂₄R25)q-

(NH)_tX",

-(CR₂₀R₂₁)_m(CR₂^N-NR₃₀)_I1 ^»A"_m,<CR₂₂R₂₃)_J1(OCH₂CH₂)_p(CR₄₀R4₁)_p.Y"(CR₂₄R25)_q-X", preferably -(C=0)_p»{CR₂oR₂₁)_m(C₄-C₇-cydoalkyl)_t<CR₂₂R₂₃)_J1(2,5- dioxopyiTolidiiiyl)_p(CR₂₄R₂₅)_p-X", or

cycloalkyl)t<CR₂₂R₂₃)_a(2 ,5 -dioxopyiTolidiiiyl)_p(CR₂₄R25)p'X" , wherein:

m, n, p, q, in', n', t' for each occurrence are independently integer from 1 to 10, 2 to 9, 3 to 8 or are optionally 0;

t, in", n" and p" for each occurrence independently are 0 or 1 ; X" is a bond to P_p, or a bond to a cysteine, preferably the sulphur group of said cysteine, wherein the cysteine is bound to P_p, optionally the carbonyl-group of said cysteine is substituted by a carboxamide group;

Y" is absent or is selected from O, S, S— S or NR₃₂, wherein R₃₂, for each occurrence, is independently selected from the group consisting of— H, an optionally substituted linear, branched or cyclic alkyl, alkenyl or alkynyl having from 1 to 10 carbon atoms, a polyethylene glycol unit— (CH₂CH₂0)n— Rc, an optionally substituted aryl having 6 to 18 carbon atoms, an optionally substituted 5- to 18-membered heteroaryl ring containing one or more heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an optionally substituted 3- to 18-membered heterocyclic ring containing 1 to 6 heteroatoms independently selected from O, S, N and P, or

when Y" is not S— S and t=0, X" is selected from a maleimido group, a haloacetyl group or SR37, wherein R₃₇ has the same definition as above;

A" is an amino acid selected from glycine, alanine, leucine, valine, lysine, citralline and glutamate or a polypeptide containing between 2 to 20 amino acid units;

R₂₀, R_2I, R₂₂, ₂₃, R_24; R₂₅, R₂₆ and R₂₇ are the same or different and are H or a linear or branched alkyl having from 1 to 5 carbon atoms;

R₂₉ and R₃₀ are the same or different and are H or alkyl from 1 to 5 carbon atoms;

R₃₃ is H or linear, branched or cyclic alkyl, alkenyl or alkynyl having from 1 to 12 carbon atoms, a polyethylene glycol unit— (OCH₂CH₂)_n, or R₃₃ is— COR₃₄,— CSR₃₄,— SOR₃₄, or — S0₂R₃₄, wherein R₃₄ is H or linear, branched or cyclic alkyl, alkenyl or alkynyl having from 1 to 20 carbon atoms or, a polyethylene glycol unit— (OCH₂CH₂)_n; and

one of R₄₀ and R₄₁ is optionally a negatively or positively charged functional group and the other is H or alkyl, alkenyl, alkynyl having 1 to 4 carbon atoms; or

is selected from the group consisting of: ethylenediainine, SMCC (succinimidyl 4-(N- maleimidomethyl)cyclohexane- 1 -carboxylate), succinimidyl-([N- maleimidopropionamido]-(ethyleneglycol)_a)ester, wherein n is an integer between 1 to 10, preferably the linker is ethylenddiamine or SMCC.

11. The antibiotics of any one of items 1 to 10, which have at least one of the following properties:

(i) a minimal inhibitory concentration (MIC) that is at least 50% lower than the MIC of the respective antibiotic without the coupled polypeptide; preferably for conjugates of vancomycin of 8 mg/L or less against E. faecium VanA UL602570, E. faecium VanA UL407074, E. faecalis VanO ATCC29212, E. faecalis VanB SC413687, E. faecalis VanB ATCC 51299, E.faecium VanB UL405955, E. casseliflavus VanC ATCC 700327 and E. gallinamm VanC AL40 773;

(ii) a cytotoxicity against human peripheral blood mononuclear cells (PBMCs) of less than

10% at the MIC;

(iii) a plasma half-life that is at least 50% longer than the respective antibiotic without the coupled polypeptide and linker if present;

(iv) a cytotoxicity against human liver cells of less than 10% at the MIC, preferably less than 10% cytotoxicity at 64pg/ml; and/or

(v) a cytotoxicity against human kidney cells of less than 10% at the MIC, preferably less than 10% cytotoxicity at 64pg/ml.

12. An antibiotic of any one of items 1 to 11 for use In the treatment or prophylaxis of a bacterial infection.

13. The antibiotic for use of item 12, wherein the bacterial infection is with a bacterium selected from the group consisting of a gram negative and gram positive bacterium, preferably a vancomycin-resistant bacteria, in particular Enterococci , Staphylococci, or Streptococci , wherein the bacterial infection is preferably with a multiple drug resistant bacterium (MRS A), preferably Staphylococci, E.faecium , E. faecalis, or E. gallinamm.

14. The antibiotic for use of item 12 or 13 in combination with one or more antibiotics selected from the group consisting of glycopeptides, tetracyclines, aminoglycosides, and cephalosporines.

15. An antibiotic of any one of items 1 to 11 for use as a medicament.

Claims

1. An antibiotic comprising at least one polypeptide of a length of 2 to 20 amino acids, preferably of a length of 2 to 12 amino acids, wherein the N-tenninus of the polypeptide is not attached to a lipophilic group and the polypeptide is positively charged and optionally a linker connecting the antibiotic and the polypeptide.

2. The antibiotic of claim 1, wherein the antibiotic core is selected from the group consisting of a glycopeptide antibiotic; a cyclic lipopeptide antibiotic; a B- actam antibiotic, preferably a cephalosporine antibiotic; an oxazolidinone antibiotic; and an aminoglycoside antibiotic.

3. The antibiotic of claim 2, wherein the:

(i) glycopeptide antibiotic is selected from the group consisting of vancomycin, teicoplanin, A477, A35512, A40926, A41030, A42867, A47934, A80407, A82846, A83850, A84575, AB-65, actaplanin, actinoidin, ardacin, avoparcin, azureomycin, balhimycin, chloroorientiein, chloropolysporin, dalbavancin, decaplanin, N- demethylvancomycin, eremomycin, galacardin, helvecardin, izupeptin, kibdelin, LL- AM374, mannopeptin, MM45289, MM47756, MM47761, MM49721, MM47766, MM55260, MM55266, MM55270, MM56597, MM56598, OA-7653, orenticin, parvodicin, ristocetin, ristomycin, synmonicin, telavancin, UK-68597, UK-69542, and UK-7205 or antibiotic structural analogs thereof;

(iii) aminoglycoside antibiotic is selected from the group consisting of amikacin or kanamycin;

(iv) b-lactam antibiotic is selected from the group consisting of penicillin amoxicillin, and ampicillin;

(v) cephalosprine antibiotic is selected from the group consisting of cefazolin, cefadroxil, cephalexin, cefuroxim, cefotiam, cefaclor, cefuroxim, loracarbef, cefixim, cefpodoxim, ceftibuten, cefotaxim, ceftriaxon, ceftazidim, cefepim ceftobiprol, ceftolozan, ceftarolin; and

(vi) oxazolidinone antibiotic is linezolid.

4. An antibiotic of one of the structures (I) or (II)

wherein:

L is a linker;

X_j is selected from: -OH, -(NH)_r-(CH₂)_s-N-(CH₂)₂, -P_P or -L-P_P,

X₂ is selected from structure (

wherein Y₃ is selected from -H, -OH, and -NH-Y₉,

wherein Y₉ is selected from -H, -(CH₂)_¥-NH₂, -(CH₂)_¥-NH-(CH₂)_W-CH₃, chlorobiphenyl, -P_p and -L -P_P, wherein v is an integer ranging from 1 to 4, w is an integer ranging from 6 to 12, P_p is said polypeptide and L is said linker, wherein Y₂ is selected from -H and -CH₃,

wherein Y₆ is selected from -H, and -0-Y₈, wherein Y₈ is a substituted tetrahydrofuranyl, preferably a substituted tetrahydrofuranyl-3-4-diol, more preferably 2-(hydroxymethyl)tetrahydrofuranyl-3-3- diol,

wherein Y₃ is a branched or unbranched C₈ to C alkyl or alkenyl, preferably a C₉ alkenyl or a C_u alkyl;

X₃ is selected from - X₁₄-CH₃ and -NH-X₁₅,

wherein X₁₄ is selected from -H, -P_p and -L-P_p,

wherein X₁₅ is selected from -H, -P_p and -L-P_p;

X4 is selected from -H, -P_p, -L-P_p and a substituted phosphonic acid, preferably substituted methylamino-phosphonic acid;

X₅ is selected from -H, or substituted tetrahydropyranyl, preferably amino-methyl- hydroxy-tetrahydropyranyl or (dihydroxy-hydroxymethyl-tetrahydropyran)-acetamide;

¾ is selected from -H, -Cl, -F, -Br, and -I;

X₇ is selected from -H, -Cl, -F, -Br, and -I;

X₈ is selected from -H and -O-Y ₁₀,

X₉ is selected from -H and substituted tetrahydropyranyl, preferably hydroxymethyl— trihydroxy-tetrahydropyranyl or (methylacetate)-trihydroxytetrahydro-pyranyl ;

X₁₀ is selected from acetamide and substituted or unsubstituted phenyl, preferably phenyl or halobenzyl, and X_n is selected from C₃ to C₆ alkyl, preferably a C₄ alkyl, substituted phenyl, preferably methyl-trihydroxy-tetrahydropyranyl substituted phenyl;

or

X_l0 and Xn are linked by a unsubstituted or substituted diphenyl ether, preferably a substituted or unsubstituted hydroxyphenoxy-phenyl, more preferably hydroxyphenoxy-phenyl, halo-hydroxyphenoxy-phenyl or methyl-hydroxyphenoxy- phenyl;

X₁₂ is selected from -CH₂-OH, -COOH, -0-Y_u ,

wherein the antibiotic of (I) comprises at least one P_p;

or

wherein Wi is selected from -P_p or -L-P_p.

5. The antibiotic according to claim 4, wherein the positively charged polypeptide (P_p) or the linker forms a bond to

(i) the indicated residues of structure (I):

wherein:

Xx is selected from -OH,

, -P_p or -L-Pp, wherein P_p is said polypeptide and L is said linker, with the proviso that the N-teiminus of P_p is preferably not attached to a lipophilic group;

X₂ is selected from structure (PI), or - H-CO-Y₃, wherein Uc is selected from -H, -OH,

₃ -P_p or -L-Pp, wherein P_P is said polypeptide and L is said linker,

wherein Y₂ is -H, -C¾,

wherein Y₃ is a branched or unbranched C₈ to C₁₂ alkyl or alkenyl, preferably a C₉ alkenyl or a C_u alkyl,

wherein Y₆ is selected from -H or

X₃ is selected from -NX₁₄-CH₃ or -NH-X₁₅,

wherein X_l4 is selected from -H, -P_P or -L-P_P, wherein P_P is said polypeptide and

L is said linker,

wherein X₁₅ is selected from -H, -P_p or -L-Pp, wherein P_p is said polypeptide and L is said linker;

X₄ is selected from -H, , -P_P or -L-P_P, wherein P_P is said polypeptide and L is said linker;

X₅ is selected from -H

Xe is selected from -H, -Cl;

X₇ is selected from -H, -Cl;

X₈ is selected from -OH, -H, or

X₉ is selected from -H or , wherein Y₇ is selected from -H or -CO-C¾;

X 10 is selected from , wherein is selected from -H or -Cl, and X_n is selected from C₃ to C₆ alkyl, preferably a C₄ alkyl,

or

X₁₀ and X_u are linked by , whereby Y₄ is selected from -H, -G¾, or -Cl;

X₁₂ is selected from -CH₂-OH, -COOH or

6. The antibiotic of any one of claims 4 and 5, wherein the positively charged polypeptide comprises 2 to 30, preferably 2 to 15, lysine and/or arginine residues.

7. The antibiotic of any one of claims 1 to 3, wherein the polypeptide or the linker forms a bond to

(i) the indicated residues of structure (I):

wherein:

Xx is selected from: -OH, -(NH)_r-(CH₂)_s-N-(CH₂)₂, -P_P or -L-P_P,

wherein P_P is said polypeptide and L is said linker, with the provisio that the N- terminus of P_P is preferably not attached to a lipophilic group;

X₂ is selected from structure (PI), or -NH-CO-Y₃,

wherein Uc is selected from -H, -OH, -NH-Y₉,

wherein Y₉ is selected from -(CH₂)_¥-NH-(CH₂)_w-CH₃,chlorobiphenyl, -P_p or -L- P_p, wherein v is an integer ranging from 1 to 4, w is an integer ranging from 6 to 12, P_p is said polypeptide and L is said linker,

wherein Y₂ is -H or -CH₃,

wherein Y₆ is selected from -H, -0-Y₈,

wherein Y₈ is a substituted tetrahydrofuranyl, preferably a substituted tetrahydrofuranyl-3-4-diol, more preferably 2-

(hydroxymethyl)tetrahydrofuranyl-3-3-diol,

wherein Y₃ is a branched or unbranched C₈ to Ci₂ alkyl or alkenyl, preferably a C₉ alkenyl or a C_u alkyl;

X₃ is selected from -NX₁₄-CH₃ or -NH-X₁₅,

wherein X₁₄ is selected from -H, -P_p or -L-P_p,

wherein P_p is said polypeptide and L is said linker,

wherein X₁₅ is selected from -H, -P_p or -L-P_p,

wherein P_p is said polypeptide and L is said linker;

X4 is selected from -H, -P_p, -L-P_p or a substituted phosphonic acid, preferably substituted methylamino-phosphonic acid,

wherein P_p is said polypeptide and L is said linker; X₅ is selected from -H, or substituted tetrabydropyranyl, preferably amino-methyl- hydroxy-tetrahydropyranyl or (dihydroxy-hydroxymethyl-tetrahydropyran)- acetamide;

¾ is selected from -H, -Cl, -F, -Br, -I;

X₇ is selected from -H, -Cl, -F, -Br, -I;

X₈ is selected from -H or -O-Y ₁₀,

X₁₂ is selected from -C¾-OH, -COOH, -0-Y_u ,

(ii) the indicated residues of structure (P):

8. The antibiotic of any of claims 1 to 7, wherein the linker or the polypeptide is conjugated to:

(i) a primary or secondary amine of the antibiotic, preferably fanning a peptide bond between antibiotic and the linker or the polypeptide;

(ii) a carboxy group of the antibiotic, preferably forming a peptide bond or an ester bond between the antibiotic and the linker or the polypeptide;

(iii) a hydroxyl group of the antibiotic, preferably forming an ester bond or ether bond between the antibiotic and the linker or the polypeptide.

9. The antibiotic of any one of claims 1 to 8, wherein the polypeptide is linear or circular and:

1); RRRRR (SEQ ED NO: 2), RRRR (SEQ ID NO: 3), RRR, RRRRRRR (SEQ ID NO: 4), RRRRRRRR (SEQ ID NO: 5), RRRRRRRRR (SEQ ED NO: 6), RRRRRRRRRR (SEQ ID NO 7), RRRRRRRRRRR (SEQ ID NO: 8), RRRRRRRRRRRR (SEQ ID NO: 9), RRRRRRC (SEQ ID NO: 10); RRRRRC (SEQ ID NO: 11), RRRRC (SEQ ID NO: 12); RRRC (SEQ ID NO: 13), RRRRRRRC (SEQ ID NO: 14), RRRRRRRRC (SEQ ID NO: 15), RRRRRRRRRC (SEQ ID NO: 16), RRRRRRRRRRC (SEQ ID NO 17), RRRRRRRRRRRC (SEQ ED NO: 18), RRRRRRRRRRRRC (SEQ ED NO: 19); RRK, RKR, RKK, KRK, KKR, RRRK (SEQ ID NO: 20), RRKR (SEQ ID NO: 21), RKRR (SEQ ID NO: 22), KRRR (SEQ ED NO: 23), RRKK (SEQ ED NO: 24), RKRK (SEQ ID NO: 25), KRKR (SEQ ID NO: 26), RKKR (SEQ ED NO: 27), KKRR (SEQ ID NO: 28), KRRK (SEQ ED NO: 29), KKKR (SEQ ID NO: 30), KKRK (SEQ ID NO: 31), KRKK (SEQ ID NO: 32), RKKK (SEQ ID NO: 33), KKKK (SEQ ED NO: 34), RRRKK (SEQ ID NO: 35), RRRKKK (SEQ ED NO: 36), CRRR (SEQ ID NO: 37), CRRRR (SEQ ED NO: 38); CRRRRR (SEQ ED NO: 39), CRRRRRR (SEQ ID NO: 40); CRRRRRRR (SEQ ID NO: 41), CRRRRRRRR (SEQ ID NO: 42), CRRRRRRRRR (SEQ ID NO: 43), CRRRRRRRRRR (SEQ ED NO: 44), CRRRRRRRRRRR (SEQ ED NO: 45), and CRRRRRRRRRRRR (SEQ ID NO: 46), KKKKKKC (SEQ ED NO: 47), and RRRKKKC (SEQ ID NO: 48) and/or

10. The antibiotic of any one of claims 1 to 9, wherein the antibiotic or the linker is coupled to the N- or C-terminus of the polypeptide or to the side chain of an amino acid of the polypeptide.

11. The antibiotic of any one of claims 1 to 10, wherein the optional linker when present is selected from the group consisting of:

-O(CR₂₀R₂₁)_m(CR_{22 23})_n(OCH₂CH₂)_p(CR₄₀R_4i)_p"Y"(CR₂₄R₂₅)_q(C=O)_tX"

-0(CR₂oR_2i)_ra(CR₂₂R₂₃)_n(OCH₂CH₂)_p(CR₄oR_4i)_P»Y"(CR₂₄R₂₅)_q(NH)_tX'',

-O(CR₂₀R₂₁)_m(CR₂₂R₂₃)_n(OCH₂CH₂)_p(CR₄₀R_4i)_P»Y"(CR₂₄R₂₅)_qX"

-O(CR₂₀R₂₁)_ni(CR_2i=CR₂₇)_m CR₂₂R₂₃)_n(OCH₂CH₂)_p(CR₄₀R₄₁)_p,-Y"(CR₂₄R₂₅)_q(C=O)_tX",

-O(CR₂₀R_2i)_m(a%iiyl)_I1<CR₂₂R₂₃)_aCOCH₂CH₂)_p(CR₄₀R_4i)_P"Y"(CR₂₄R₂₅)_q(C=O)tX",

-O(CR₂₀R₂₁)_ni(alkyiiyl)_I1<CR₂₂R₂3MOCH₂CH₂)_p(CR4_£)R4i)_P*Y^f'(CR24R2₅)_q(NH)_tX",

-O(CR₂₀R₂₁)_m(alkynyl)_I1<CR₂₂R₂₃)_n(OCH₂CH₂)_p(CR₄₀R₄₁)_p.Y"(CR₂₄R₂₅)_qX",

-O(CR₂₀R₂₁)_ra(piperaziiio)_t<CR₂₂R₂₃)_:I1(OCH₂CH₂)_p(CR₄₀R₄₁)_p»Y"(CR₂₄R₂₅)_q(C=O)_fX",

-0(CR₂oR₂₁)₁₁₁(piperaziiio)_f(CR₂₂R₂₃)_I1(OCH₂CH₂)_p(CR₄₀R_4i)_P»Y"(CR₂₄R₂₅)_q(NH)_tX"

-O(CR₂₀R₂₁)_m(piperaziiio)_t<CR₂₂R₂₃)_n(OCH₂CH₂)_p(CR₄₀R₄₁)_p-Y"(CR₂₄R25)_tlX"

-O(CR₂₀R₂₁)_m(pyiiOlo)_t<CR₂₂R₂₃)_fl(OCH₂CH₂)_p(CR₄₀R₄₁)_pY^r"(CR₂₄R₂₅)_q(C=O)_tX",

-O(CR₂₀R₂₁)_m(pyiTolo)_t<CR₂₂R₂₃)_:[1(OCH₂CH₂)_p(CR₄₀R₄₁)_pY"(CR₂4R2₅)_q(NH)_tX",

-O(CR₂₀R₂₁)_m(pynOlo)_t<CR₂₂R₂₃)_I1(OCH₂CH₂)_p(CR₄₀R₄₁)_pY^r,'(CR₂₄R₂₅)_qX",-

0(CR₂oR₂₁)_mA''_m-<CR₂₂R₂₃)_n(OCH₂CH₂)_p{CR₄₀R_4i)_p»Y''(CR₂₄R₂₅)_q(C=0)_tX",

-0(CR₂oR₂₁)_mA"_m»(CR₂₂R₂₃)_n(OCH₂CH₂)_p(CR₄oR_4i)_p-Y"{CR₂₄R₂₅)_q(NH)_tX",

-O(CR₂₀R₂₁)_mA"_m CR₂₂R₂₃)_H(OCH₂CH₂)_p(CR4₀R4i)_P-Y^,'(CR₂₄R25)_qX",

-S(CR₂₀R₂₁)_m(CR₂₂R₂₃)_n(OCH₂CH₂)_p(CR₄₀R_4i)_P*Y"(CR₂₄R₂₅)_q(C=O)_tX",

-S(CR₂₀R₂₁)_m(CR₂₂R₂₃)_n(OCH₂CH₂)_p(CR₄₍₎R₄₁)_p»Y"(CR₂₄R₂₅)_q(NH)_tX"_;

-S(CR₂₀R₂₁)_m(CR₂₂R₂₃)_n(OCH₂CH₂)_p(CR4oR4i)p-Y"(CR₂₄R25)qX",

-S(CR₂₀R₂₁)_m(CR₂₆=CR₂₇)_ni<CR₂₂R₂₃)_n(OCH₂CH₂)_p(CR₄₀R₄₁)_p»Y"(CR₂₄R₂₅)_q(C=O)_tX",

-S(CR₂₀R₂₁)_m(CR₂₆=CR₂₇)_m<CR₂₂R₂₃)_n(OCH₂CH₂)_p(CR₄₀R₄₁)_P»Y"(CR₂₄R₂₅)_q(NH)_tX",

-S(CR₂oR₂₁)_ni(CR₂₆=CR₂₇)_m CR₂₂R₂₃)₁₁(OCH₂CH₂)_p(CR₄₀R₄₁)_p»Y"(CR₂₄R₂₅)_qX",

-S(CR₂₀R₂₁)_m(alkyiiyl)_n<CR₂₂R₂₃)_n(OCH₂CH₂)_p(CR₄₀R₄₁)_p„Y"{CR₂₄R₂₅)_q(C^))_tX",

-S(CR₂₀R₂₁)_ni(alkyiiyl)₁₁<CR₂₂R₂₃)₁₁(OCH₂CH₂)_p(CR4oR_4i)_p-Y"(CR₂4R₂5)_q(NH)_tX",

-S(CR₂₀R2₁)_ni(alkyiiyl)_n<CR₂₂R₂₃)_n(OCH₂CH₂)_p(CR4oR_4i)_p-Y"{CR₂4R₂₅)_qX",

-S(C ₂o ₂₁)_m(piperaziiio)_t'{C _{22 23})_n(OCH₂CH₂)_p(C ₄o _i)_p' "(CR₂₄R₂₅)_q(C=0)_t ",

-S(CR₂₀R₂₁)_ni(piperazmo)_t,(CR₂₂R₂₃)_I1(OCH₂CH₂)_p(CR₄₀R₄₁)_p-Y"{CR₂₄R₂₅)_q(NH)_tX",

-S(CR₂₀R₂₁)_m(iMperazmo)_t<CR₂₂R₂3)_n(OCH₂CH₂)_p(CR₄₀R₄₁)_p.Y"{CR₂₄R₂₅)_qX",

-S(CR₂₀R₂₁)_ni(i yiTolo)_t<CR₂₂R₂₃)_a(OCH₂CH₂)_p(CR₄oR₄₁)_p»Y"(CR₂₄R₂₅)_q(C=A))_tX",

-S(CR₂oR₂₁)_m(pyiTolo)_t-(CR₂₂R₂₃)_n(OCH₂CH₂)_p(CR₄oR4i)_p» ^Y"(CR₂₄R₂₅)_q(NH)_tX",

-S(CR₂₀R₂₁)_m(pynOlo)_t<CR₂₂R₂₃)_n(OCH₂CH₂)_p(CR₄₀R₄₁)_p-Y"(CR₂₄R₂₅)_qX'',

-S(CR₂₀R₂₁)_mA"_m"(CR₂₂R₂₃)_n(OCH₂CH₂)_p(CR₄₀R4i)_P ^»Y"(CR₂₄ ^R2₅)_qX",

-NR₃₃(C=O)_p.<CR₂₀R₂₁)_m(CR₂₂R₂₃)_n(OCH₂CH₂)_p(C:R₄₀R_4i)_P'Y"(CR₂₄R₂₅)_q(C=O)_tX^f',

-NR₃₃(C=0)_p»(CR₂oR_2i)_m(CR₂₂R₂₃)_I1(OCH₂CH₂)_p(CR₄₀R_4i)_p»Y^w(CR₂₄R₂₅) _I(NH),X",

-NR₃₃(C=O)_p CR₂₀R₂₁)_ni(CR₂₂R₂₃)_n(OCH₂CH₂)_p(CR₄₀R₄₁)_p.Y"(CR2₄R25)_qX", -NR₃₃(C=O)_p, CR₂₀R₂₁)_m(CR₂₆=CR₂₇)_ni<CR₂₂R₂₃MOCH₂CH₂)_p(CR₄₀R₄₁)_p-Y"(CR₂₄R₂₅)_q-(

0=0)_tX",-

NR33(C=O)p CR₂₀R_2l)_m(CR2₆=CR27)m<CR₂₂R₂₃)_n(OCH₂CH₂)p(CR40R4l)p^»Y"(CR₂₄R2₅)q-

(NH)_tX",

-NR₃₃(C=O)_p CR₂₀R₂₁)_m(CR₂₆=CR₂₇)_m<CR₂₂R₂₃)_n(OCH₂CH₂)_p(CR₄₀R₄₁)_p ^»Y"(CR₂₄R25)_q-

X",

-NR₃₃(C=0)_p.-(CR₂oR_2i)_m(alkyiiyl)_n'(CR₂₂R₂₃)_n(OCH₂CH₂)_p(CR₄oR₄₁)_p»Y"(CR₂₄R₂₅)_q-(

C=0) X",

-NR₃₃(C=O)_p, CR₂₀R₂₁)_m(alkyiiyi)_I1'(CR2₂R₂3)_n(OCH₂CH₂)_p(CR₄₀R₄₁)_p»Y"(CR₂₄R₂₅)_q-

(NH)_tX",

NR₃₃(C=0)_p»(CR₂₀R₂₁)_m(alkyiiyl)_:Ii.(CR₂₂R₂₃)_n(OCH₂CH₂)_p(CR₄oR₄₁)_p»Y"(CR₂₄R₂₅)_qX'',

-NR₃₃(C=O)p CR₂₀R₂₁)_m(piperazmo)t<CR₂₂R₂₃)_n(OCH₂CH₂)_p(CR40R4i)_P"Y"(CR₂₄R25)q-(

C=0)_tX",

-NR₃₃ (C=0)p_" (CR₂oR_{2 l})m(pip Crazino)f (C ₂₂R23)n(OC H₂C H₂)p(CR4oR4l)p_"Y" (C _{24 25})q- (NH)_tX",

-NR₃₃(C=O)_p,<CR_2i)R₂₁)_ni(piperazmo)_r(CR₂₂R₂₃)_n{OCH₂CH₂)_p{CR₄₀R₄₁)_p-Y"(CR₂₄R₂₅)_qX",

-NR3₃(C=O)_p CR₂₀R₂₁)_m(pynOlo)_f(CR₂₂R₂3)_n(OCH₂CH₂)_p(CR₄₀R₄₁)_p.Y"{CR₂₄R₂₅)_q~ (

C=0)_tX",

.(C=O)_p,(CR₂₀R₂₁)_m(CR₂₂R₂₃)_I1(OCH₂CH₂)_p(CR₄₀R_4i)_p»Y"(CR₂₄R₂₅)_q(NH)_tX",

-(C=0)_p ^»(CR₂oR_2i)_m(CR₂₂R₂₃)_:I1(OCH₂CH₂)p(CR4₀R4i)p^»Y"(CR₂₄R₂₅)qX"

C=0)_tX",

-(C=O)_p»(CR₂₀R₂₁)_m(alkyiiyl)₁₁<CR₂₂R₂₃)_n(OCH₂CH₂)_p(CR₄₀R₄₁)_p»Y"(CR₂4R25)_q-(NH)_tX",

-(C=O)_p.(CR₂₀R₂₁)_m(alkyiiyl)_n<CR₂₂R₂₃)_n(OCH₂CH₂)_p(CR₄₀R₄₁)_p,Y"(CR₂₄R₂₅)_qX",

-(C=O)_p.(CR₂₀R₂₁)_m(piperazmo)_t<CR₂₂R₂₃)_J1(OCH₂CH₂)_p(C:R₄₀R₄₁)_P*Y"(CR₂₄R₂₅)_q-(

C=0)_tX",

-(C=O)_p.(CR₂₀R₂₁)_m(piperaziiio)_t<CR₂₂R₂₃)_n(OCH₂CH₂)p(CR4₀R4i)p-Y"(CR₂₄R₂₅)_q-

(NH)_fX",

-(C=0)_p.(CR₂oR_2i)_m(piperazmo)t<CR₂₂R₂₃)₁₁(OCH₂CH₂)₁ (CR4oR4i)_P ^»Y"(CR24R25)_qX",

-(C=0)_p,(CR₂oR₂₁)_m(PyiTolo)_r(CR₂₂R₂₃)₁₁(OCH₂CH₂)_p(CR₄oR₄₁)_p»Y"(CR₂₄R₂₅)_tl- (

C=0)_tX",

-(C=O)p^»(CR₂o ₂₁)_m(pyiTelo)t (CR_{22 23})n(OCH₂CH₂)p(C 40R4i)_p ^»Y"(CR₂₄R₂₅)q (NH)_tX", -(C=O)_p»(CR₂₀R₂₁)_m(pynOlo)_f(CR₂₂R₂₃)₁₁(OCH₂CH₂)_p(CR₄₀R₄₁)_P»Y"CCR₂₄R₂₅)_qX"_J -(C=0)_p»(CR₂oR₂₁)_m(C₄-C₇-cycloalkyl)_r(CR₂₂R₂₃)_I1(2,5- dioxopyiTolidiiiyl)

-(C=O)_p»(CR₂₀R_{2 i})_H1(C₄-C₇-cycloalkyl)_r(CR₂₂R₂₃)₁₁(2, 5 - dioxopyiTolidiiiyl)_p(CR₂4R25)_p''(NH)_t X” ,

-(C=O)_p«(CR₂₀R_{2 i})_m(C₄-C₇-cycloalkyl)t<CR₂₂R₂₃)_n(2, 5 -dioxopyrrolidinyl)_p(CR₂₄R₂s VX" ,

-(C=0)_p»(CR₂oR_2i)_mA"_m™(CR₂₂R₂₃)₁₁(OCH₂CH₂)_p(CR₄₀R_4i)_P-Y"(CR₂₄R₂₅)_q(C=0)tX",

-(C=O)_p,(CR₂₀R₂₁)_inA"_m»(CR₂₂R₂₃)_I1(OCH₂CH₂)_p(CR₄₀R₄₁)_p»Y"(CR₂₄R₂₅)_q(NH)_tX",

-(C=O)_p-(CR₂₀R₂₁)_inA"_m CR₂₂R₂₃)₁₁(OCH₂CH₂)_p(CR₄₀R₄₁)_p.Y"(CR₂₄R₂₅)_qX"

-(CR₂₀R₂₁)_m(CR₂₂R₂₃)_n(OCH₂CH₂)_p(CR₄oR_4i)_p.Y"(CR₂₄R₂₅)_q(C=0)_tX",

-(CR₂₀R₂₁)_m(CR₂₂R₂₃)_n{OCH₂CH₂)_p(CR₄oR_4iVY"(CR₂₄R₂₅)_q(NH)_tX"

-(CR₂₀R₂₁)_m(CR₂₂R₂₃)_n(OCH₂CH₂)_p(CR₄₀R₄₁)_p-,Y”(CR₂₄R₂₅)_£1X",

-(CR₂₀R₂₁)_m(CR₂₆=CR₂₇)_m<CR₂₂R₂₃)_I1(OCH₂CH₂)_p(CR4oR4i)_P'Y"(CR₂₄R25)qX"

-(CR₂oR₂₁)_m(alkyiiyl)_n<CR₂₂R₂₃)_H(OCH₂CH₂)_p(CR_4i,R_4i)_P»Y"(CR₂₄R₂₅)_q(C=0)_tX",

-(CR₂₀R₂₁)_ni(alkyiiyl)_!1<CR₂₂R₂₃)_n(OCH₂CH₂)_p(CR₄oR4i)_P»Y^,'(CR₂₄R₂5)_q(NH)_tX",

-(CR₂₀R₂₁)_ni(alkyiiyl)₁₁<CR₂₂R₂₃)_I1(OCH₂CH₂)_p(CR₄₀R4₁)_p-Y"(CR₂₄R₂₅)_qX", -(CR₂₀R₂₁)_ni(piperaziiio)_t<CR₂₂R₂₃)_n(OCH₂CH₂)_p(CR₄₀R₄₁)_p»Y"(CR₂₄R₂₅)_q(C=0)_tX", -(CR₂₀R₂₁)_m(piperaziiio)_t<CR₂₂R₂₃)_n(OCH₂CH₂)_p(CR₄₀R₄₁)_p'-Y"(CR₂₄R₂₅)_q(NH)_tX"

(CR₂₀R_{2 i})_m(piperazmo)_t'(CR₂₂R₂3)_n(OCH₂C H₂)_P(C R40 41 )_p" Y” (CR₂₄R₂5)_qX" ,

-(CR₂oR₂₁)_mA"_m"(CR₂₂R₂₃)_a(OCH₂CH₂)_p(CR₄oR_4i)_p»Y"(CR₂₄R₂₅)_q(C=X⁾)_tX",

(CR₂₄R₂₅)_q(C=0)_tX",

-(CR₂o ₂₁)_m(CR_2ί =N-N ₃o)_n-(CR₂₆=CR₂₇)₁₁₁<C _{22 23}MOCH₂CH₂)_p(C ₄₀R4l)_P ^»Y^,,- (CR₂₄R₂₅)_q(NH)_tX" ,-{CR₂₀R_{2 i})_m(CR₂₉=N-

NR30 (CR₂₆=C ₂ )_m'(CR_{22 23})_n(OCH₂CH₂)_p(C {) )_P«Y " - (CR₂₄R₂ )_qX " ,

-(CR₂₀R₂₁)_m(CR₂₉N-NR₃₀)_n<alkyiiyl)_n'(CR₂₂R₂₃)_n(OCH₂CH₂)_p(CR₄₀R_4i)_P»Y"(CR₂₄R₂₅) (

C=0)_tX",

-(CR₂₀R₂₁)_m(CR₂₉N-NR₃₀)_n<alkyiiyl)_n<CR₂₂R₂₃)₁₁(O€H₂CH₂)_p(CR₄₀R₄₁)_p-Y"(CR₂₄R₂₅)

(NH)_tX",

- (CR₂₀R₂₁ )_m(CR₂₉N-NR₃o)_n'( alkyiiyl)_n(CR₂₂R₂₃ )_n(OCH₂C H₂)_P(C ₄oR_4i)_p"Y " (CR₂₄R₂₅)_q-X' ,

-(CR₂₀R₂₁)_ni(CR₂^N-NR₃o)_nA"_ni™(CR₂₂R₂₃)_n(OCH₂CH₂)_p(CR_4{)R₄₁)_p.Y"(CR₂₄R₂₅)_£1-

(C=0)_tX",

-(CR₂₀R₂₁)_m(CR₂₉=N-NR₃o)_nA"_m-<CR₂₂R₂₃)_n(OCH₂CH₂)_p(CR₄oR_4i)_P»Y"(CR₂₄R₂₅)_q-

(NH)_tX",

-(CR₂₀R₂₁)_m(CR₂^=N-NR₃o)_nA"_m CR₂₂R₂₃)_D(OCH₂CH₂)p(CR4oR4i)_P ^»Y"CCR₂₄R₂₅)q-X", wherein:

111, 11, p, q, in', 11', t' are integer from 1 to 10, 2 to 9, 3 to 8 or are optionally 0;

t, in", 11" and p" are 0 or 1;

X" is a bond to P_p;

Y" is absent or is selected from O, S, S— S or NR₃₂, wherein R₃₂ R, for each occurrence, is independently selected from tlie group consisting of— H, an optionally substituted linear, branched or cyclic alkyl, alkenyl or alkynyl having from 1 to 10 carbon atoms, a polyethylene glycol unit— (CH₂CH₂0)n— Rc, an optionally substituted aryl having 6 to 18 carbon atoms, an optionally substituted 5- to 18-membered heteroaryl ring containing one or more heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an optionally substituted 3- to 18-membered heterocyclic ring containing 1 to 6 heteroatoms independently selected from O, S, N and P, or

when Y" is not S— S and t=0, X" is selected from a maleimido group, a haloacetyl group or SR₃₇, wherein R₃₇ has the same definition as above;

A" is an amino acid selected from glycine, alanine, leucine, valine, lysine, citrulline and glutamate or a polypeptide containing between 2 to 20 amino acid units;

R₂₀, R₂I, R₂₂, R₂₃, R₂₄, R₂₅, R₂₆, and R₂₇ are the same or different and are H or a linear or branched alkyl having from 1 to 5 carbon atoms;

R₃₃ is H or linear, branched or cyclic alkyl, alkenyl or alkynyl having from 1 to 12 carbon atoms, a polyethylene glycol unit— (OCH₂CH₂)_n, or R₃₃ is— COR₃₄,—€SR₃₄,— SOR₃₄, or — S0₂R₃₄, wherein R₃₄ is H or linear, branched or cyclic alkyl, alkenyl or alkynyl having from 1 to 20 carbon atoms or, a polyethylene glycol unit— (OCH₂CH₂)_n; and

one of R₄₀ and K₄₁ is optionally a negatively or positively charged functional group and the other is H or alkyl, alkenyl, alkynyl having 1 to 4 carbon atoms; or

is selected from the group consisting of: ethyl enediamine, SMCC (succinimidyl 4-(N- maleimidomethyl)cyclohexane- 1 -carboxylate), succinimidyl-([N- maleimidopropionamidoj-iethyleneglycol^ester, wherein n is an integer between 1 to 10, preferably the linker is ethylenediamine or SMCC.

12. The antibiotics of any one of claims 1 to 11, which have at least one of the following properties:

(i) a minimal inhibitory concentration (MIC) that is at least 0% lower than the MIC of the respective antibiotic without the coupled polypeptide; preferably for conjugates of vancomycin of 8 mg/L or less against E. faecium VanA UL602570, E. faecium VanA UL407074, E. faecalis VanO ATCC29212, E. faecalis VanB SC413687, E. faecalis VanB AT CC 51299, E. faecium VanB UL405955, E. casseliflavus VanC ATCC 700327 and E. gallinarum VanC AL405773;

10% at the MIC;

(iii) a reduced kidney accumulation; and/or

13. An antibiotic of any one of claims 1 to 12 for use in the treatment or prophylaxis of a bacterial infection.

14. The antibiotic for use of claim 13, wherein the bacterial infection is with a bacterium selected from the group consisting of a gram negative and gram positive bacterium, preferably a vancomycin-resistant bacteria, in particular Enterococci, Staphylococci, or Streptococci, wherein the bacterial infection is preferably with a multiple drug resistant bacterium (MRSA), preferably Staphylococci, E. faecium, E.faecalis, or E. gallinarum.

15. The antibiotic for use of claim 13 or 14 in combination with one or more antibiotics selected from the group consisting of glycopeptides, tetracyclines, aminoglycosides, and cephalosporines .