WO2009146885A2

WO2009146885A2 - Lipidated antibacterial peptides

Info

Publication number: WO2009146885A2
Application number: PCT/EP2009/003930
Authority: WO
Inventors: Andrea Giuliani; Giovanna Pirri; Silvia Fabiole Nicoletto
Original assignee: Spiderbiotech S.R.L.
Priority date: 2008-06-02
Filing date: 2009-06-02
Publication date: 2009-12-10
Also published as: WO2009146885A3

Abstract

The present invention relates to lipidated peptidic compounds which have antimicrobial activity, particularly against Gram-positive and Gram-negative bacteria. Further, the present invention refers to compositions comprising said peptidic compounds for medical use, for use as a disinfectant and/or detergent or for use as a preservative.

Description

Lipidated antibacterial peptides

Description

The increased occurrence of multidrug resistant microorganisms has prompted renewed interest in the development of novel antimicrobial agents. The drive to produce newer agents targeting novel sites that may circumvent resistance is critical for the long-term control of bacterial infection (Ref. 1 ).

The pharmaceutical industry has previously met this need by modifying existing antibiotics and developing newer antibiotics in a timely fashion. These successful efforts have produced the wide variety of currently available drug classes of antibiotics: beta lactams (penicillins, carbapenems, cephalosporins), glycopeptides, macrolides, ketolides, aminoglycosides, fluoroquinolones, oxazolidinones, and others (Ref. 2). Recently, however, microorganisms which are resistant against most or all of the known classes of antibiotics have been detected. Thus, there is an increased need for novel antibiotic compounds.

Antimicrobial peptides are components of the nonspecific immune system that represent a promising class of anti-infective agents. Although their mode of action is not well understood, they are believed to have multiple targets, including the cytoplasmic membrane and the processes of cell division and macromolecule synthesis (Ref. 3).

A review of peptide antibiotics has been published by R.E.W. Hancock (Ref. 4). The review focuses primarily on the advantages and disadvantages of cationic antimicrobial peptides (AMPs) when compared with conventional antibiotics, and summarizes recent clinical developments with these peptides. They can be defined as being short (10-50 amino acids), with an overall positive charge (generally +2 to +9) and a substantial proportion (>30%) of hydrophobic residues. These properties permit the peptide to fold into an amphiphilic structure in three dimensions, often upon contact with membranes, so they form separate patches rich in positively charged and hydrophobic amino acids.

AMPs exhibit a broad spectrum of killing activity in vitro against various targets, such as bacteria, fungi, enveloped viruses, parasites and even tumour cells (Ref. 5 and 6).

Within the last 15 years, almost 900 AMPs have been identified across species and are now recognized as essential components of the innate immune system (Ref. 7). Magainins, e.g. magainin 2 and PGLa, are among the best studied AMPs. They are linear peptides that were originally isolated from the skin of the African frog Xenopus laevis. Magainins are α-helical ionophores that possess two important activities: a broad antimicrobial spectrum and an anti-endotoxin activity (Ref. 8).

A large family of AMPs in mammals is represented by cathelicidins. They are AMPs bearing an amino-terminal cathepsin L inhibitor domain (cathelin). The C-terminal 37 amino acid domain of the only human cathelicidin h-CAP 18, LL-37, is an amphipathic, helical peptide that exerts broad antimicrobial activity (Ref. 9).

Various synthetic peptides have been assayed in vitro and in vivo. For example, U.S. Patent Application No.60/651 ,270 discloses antimicrobial hexapeptides and lipoderivatives thereof active against a range of pathogens. These peptides are particularly effective in the treatment of fungal and bacterial diseases in animals and demonstrate the potential to promote the bactericidal activity of conventional antibiotics, such as polymyxin B, against multidrug resistant bacteria.

WO 2006/006195 discloses antibacterial peptides, i.e. a peptide having the sequence QKKIRVRLSA (SEQ ID NO: 6). Although these peptides show antimicrobial activity, they are too unstable for practical use. Indeed, the N- terminal GIn provides pyroglutamic derivatives, the content of which increases during the product storage.

The present invention provides methods for using and making novel antimicrobial peptidic compounds to treat and/or prevent infectious diseases.

A subject-matter of the present invention is a multimeric lipidated compound comprising a plurality of antimicrobially active monomeric peptidic units connected via linkers, having a functionality of at least 2, wherein at least one lipid moiety is attached to the N- and/or C-termini of the compound.

The multimeric lipidated compound preferably comprises at least 3, and more preferably at least 4-8 antimicrobially active peptidic compounds. Further, it is preferred that the multimeric lipidated compound has a branched structure, particularly a dendritic structure. The individual monomeric peptidic units in the multimeric compound may be the same or different.

Preferred are monomeric peptidic units having a length of up to 35 amino acid residues comprising an amino acid sequence represented by the general formula (Ia):

Ai - [K]_n - K - I - R - V - R (SEQ ID NO: 31)

wherein K is an amino acid residue with a lysine side chain, particularly L- lysine, or another amino acid residue with a positively charged side chain, I is an amino acid residue with an isoleucine side chain, particularly L- isoleucine,

R is an amino acid residue with an arginine side chain or an N-alkyl substituted guanidine side chain, particularly L-arginine, V is an amino acid residue with a valine side chain, particularly L-valine, wherein one of the amino acid residues K, I, R and V may be replaced by an amino acid residue with an alanine side chain, particularly L-alanine, A₁ is the N-terminal group of the monomeric peptidic unit which comprises at least one amino acid residue and is preferably selected from

(i) an aromatic amino acid residue or a di-, tri- or tetrapeptidyl group comprising at least one aromatic amino acid residue, wherein the aromatic amino acid residue is particularly selected from tryptophane, phenylalanine, β-phenylala- nine, naphthylalanine, β-naphthylalanine, β-diphenylala- nine, β-(4,4'-biphenyl)alanine, β-anthracen-9-ylalanine and β-indol-3-ylalanine, or substituted derivatives thereof,

(ii) an aliphatic amino acid residue or a di-, tri-, tetrapeptidyl group comprising at least one aliphatic amino acid residue, wherein the aliphatic residue is particularly selected from α-amino acid residues comprising an aliphatic, preferably a branched aliphatic side chain of at least 3 C-atoms,

(iii) a pyroglutamic acid (pyrE) residue or a di-, tri- or a tetrapeptidyl group comprising an N-terminal pyroglutamic acid residue,

(iv) a residue Q* or a di-, tri- or tetrapeptidyl group comprising an N-terminal QΛresidue, wherein Q^* is an unprotected or protected amino acid residue with a glutamine side chain, particularly an unprotected or protected L-glutamine residue, and (v) combinations of any one of (i)-(iv), e.g. (i) and (iii), (i) and

(iv), (ii) or (iii) and (ii) or (iv), and n is 0 or 1.

In a preferred embodiment, the monomeric peptidic unit has a length of up to 35 amino acid residues comprising an amino acid sequence represented by the general formula (Ib):

ArlKJn-K-l-R-V-R-IAe^i-IAgl^-tAtolma (SEQ ID NO: 32),

wherein K, I₁ R, V, Ai and n are as defined above,

A₈ is an amino residue with a leucine side chain, particularly L-leucine, or an amino acid with a valine chain, particularly L-valine, A₉ is an amino acid with a serine side chain, particularly L-serine, Aio is glycine or an amino acid with an alanine side chain, particularly L- alanine, wherein one of the amino acid residues K, I₁ R, A₈ and A₉ may be replaced by an amino acid residue with an alanine side chain, and wherein ml , m2 and m3 may be independently 0 or 1.

The present invention refers to a multimeric compound comprising a plurality of monomeric peptidic units as defined above, wherein the individual peptidic units are covalently linked, e.g. by multifunctional, e.g. di- or trifunctional moieties, such as di- or trifunctional amino acids.

The term "peptidic units" encompasses compounds, which at least partially comprise amino acid building blocks or analogues thereof, which are linked by covalent bonds, perferably carboxamide bonds. The building blocks are preferably selected from amino-carboxylic acids, e.g. α-amino caboxylic acids or other types of carboxylic acids, e.g. β- or even ω-amino carboxylic acids. The amino acid building blocks may be selected from genetically encoded L-α-amino carboxylic acids and/or their D-enantiomers and/or from non-naturally occurring amino acid building blocks. The individual building blocks of the peptidic compounds are linked by covalent bonds, e.g. carboxamide, carbamate, ester and thioester bonds. The peptidic compounds of the present invention may be linear or cyclic. Monomeric peptidic compounds have a length up to 35 or 40 amino acid residues, and preferably a length of at least 6 or 8, more preferably at least 10 and up to 15 amino acid building blocks.

The monomeric units of the multimeric compounds of the invention may comprise an N-terminal group Ai which comprises an aromatic amino acid residue, preferably an α-amino acid residue comprising at least one mono- or polycyclic aromatic ring, preferably at least one bi- or tricyclic aromatic ring, e.g. phenyl, naphthyl, anthracenyl, diphenyl, indolyl, etc., or a di-, tri- or tetra-peptidyl group comprising at least one aromatic amino acid building block as described above.

Specific examples for aromatic amino acid residues are tryptophane, phenylalanine, β-phenylalanine, naphthylalanine, β-naphthylalanine, β- diphenylalanine, β-(4,4'-biphenyl)alanine, β-anthracen-9-ylalanine and β- indol-3-ylalanine, or substituted, e.g. mono- or polyalkyl substituted derivatives thereof. More preferably, the aromatic amino acid residue comprises a tryptophane side chain (W), e.g. L-tryptophane.

In a further embodiment, the monomeric peptidic units of the invention comprise an N-terminal group Ai which comprises an aliphatic amino acid residue, preferably an α-amino acid residue comprising an aliphatic, more preferably a branched aliphatic side chain of at least three C-atoms, e.g. 3, 4, 5, 6 or 7 C-atoms or a di-, tri- or tetra-peptidyl group comprising at least one aliphatic amino acid building block as described above. Specific examples for aliphatic amino acid residues are branched alkyl, e.g. methyl derivatives of 2-amino pentanoic acid, 2-amino hexanoic acid or 2-amino heptanoic acid or the L- or D-enantiomeric forms thereof. More preferably, the aliphatic amino acid residue comprises a leucine side chain (L), e.g. L- leucine. In a further embodiment of the invention, the monomeric unit comprises an N-terminal group which is a pyroglutamic acid (pyrE) residue or a di-, tri- or a tetra-peptidyl group comprising an N-terminal pyroglutamic acid residue.

In still a further embodiment of the present invention, the monomeric unit comprises an N-terminal group, which is a Q^*-residue, wherein Q* is an unprotected or protected amino acid residue with a glutamine side chain, particularly an unprotected or protected L-glutamine, or a di-, tri-, or tetra- peptidyl group comprising an N-terminal QΛresidue for a derivative thereof. Preferred examples of protected Q*- residues are dipeptidyl residues X-Q, wherein X is an amino acid residue different from Q, such as G (glycine) or a Q-residue, wherein the N-terminal amino acid and/or the carboxyl side chain group is protected, e.g. by acyl, such as acetyl groups, or linear or branched acyl groups comprising up to 25 C-atoms, e.g. from 5-25 C-atoms, amino groups etc.

In still a further embodiment, the monomeric unit of the present invention comprises a combination of an aromatic amino acid residue and an N- terminal pyroglutamic acid residue or a combination of an aromatic amino acid residue and an N-terminal Q* residue or a combination of an aliphatic amino acid residue and an N-terminal pyroglutamic acid residue or a combination of an aliphatic amino acid residue and an N-terminal Q* residue.

In an especially preferred embodiment, the N-terminal group Ai of the monomeric unit is selected from Ar, Ar-Q, Q* such as G-Q or Acetyl-Q, Q*-Ar such as G-Q-Ar or Acetyl-Q-Ar, pyrE and pyrE-Ar, wherein Ar is an aromatic amino acid residue as defined above.

Specific examples of monomeric peptidic units comprise an amino acid sequence selected from:

pyrE-KKIRVRL (SEQ ID NO 16 and 17) pyrE-KKI RVRLSA (SEQ ID NO 8, 13, 21 , 25 and 29) pyrE-KKI RVRLSG (SEQ ID NO 9, 15, 22, 26 and 30)

Acetyl-QKK\ RVRLSA (SEQ ID NO 11 )

GQKKIRVRL (SEQ ID NO 3 and 18)

GQKKIRVRLSA (SEQ ID NO 10, 14, 19, 24 and 28)

wherein pryE is a pyroglutamic acid residue and Aoa is an 8-amino octanoic acid residue.

Further preferred examples of monomeric peptidic units for the multimeric compounds of the invention are disclosed in references 4 to 9 or in US- patent application no. 60/651 ,270, the contents of which are herein incorporated by reference.

The invention refers to a multimeric compound comprising a plurality of monomeric peptidic units as described above. For example, a multimeric compound of the present invention may comprise 2, 3, 4, 5, 6, 7, 8 or more of the monomeric peptidic units. The multimeric compound may comprise the monomeric peptidic units multimerized on a matrix, e.g. a matrix based on a polypeptide, a mono-, oligo- or polysaccharide or an organic polymer, preferably a linear organic polymer. For example, the matrix may be selected from poly (N-alkyl(meth)acrylamide), poly (N, N-dialkyl(meth)acrylamide), polymelamine, dextrane, cyclodextrine, polyethyleneglycol and/or polyvinylpyrrolidone. The coupling of the monomeric peptidic units to the matrix preferably occurs via the N- and/or C-termini of the peptidic compound, e.g. using homo- and/or hetero-bifunctional linkers which allow coupling to reactive groups, e.g. hydroxy-, amino-, thiol- or carboxyl groups on the matrix.

In a further preferred embodiment, the multimeric updated compound has a branched, particularly a dendritic structure.

In a still further embodiment, the multimeric lipidated compound is selected from: [[(Ao)n1 RIn₂ Y¹Jn₃ Y² MnS (Ma)

{[(Ao)m R]n2 Y¹]n3

^ (Aθ)n5 (Hb)

wherein A₀ is a lipid moiety,

R is an antimicrobially active monomeric peptidic unit, Y¹ and Y^2' are linkers having a functionality of at least 3, Y² and Y³ are linkers having a functionality of at least 2, n1 and n5 are in each case independently 0 or 1 , wherein at least one of n1 or n5 is 1 , and n2, n3 and n4 are in each case independently whole numbers of at least 2, perferably 2, 3 or 4, more preferably 2.

R is a monomeric peptidic unit preferably as described above. Y¹ and Y^2' are linkers having a functionality of at least 3, e.g. a trifunctional amino acid, such as lysine, ornithine, nor-lysine, aminoalanine, aspartic acid or glutamic acid. Y² and Y³ are linkers having a functionality of at least 2 and preferably of at least 3, e.g. a linker as described above. A₀ is a lipid moiety present at at least one of the N-termini and/or at the C-terminus. More preferably, a lipid moiety is present at each of the N-termini and/or at the C-terminus. Even more preferably a lipid moiety A₀ is present at each of the N-termini and/or at the C-terminus. Further it is preferred that in formula (Ma) n2 and n3 are 2 and in formula (Mb) n2, n3 and n4 are 2.

The multimeric compounds (Ha) and (lib) are branched compounds, wherein individual peptidic units R are connected via linkers having a functionality of at least 3. In a preferred embodiment, the multimeric compound (Ma) comprises 4 peptidic units and has the structure:

In a further preferred embodiment, the multimeric compound (lib) comprises 8 peptidic units and has the structure:

5

In the above formula, each n1 is independently selected from 0 or 1. Preferably, n1 is 1. Further, n5 is selected from 0 or 1 with the proviso that at least one n1 , n5 is 1.

The multimeric compounds comprise at least one lipid moiety, which is preferably at least one amino carboxylic acid comprising a linear or cyclic, saturated or mono- or polyunsaturated hydrocarbon group having 3 to 25 and preferably 5 to 25 C-atoms, e.g. 5-amino valeroic acid, 8-amino octanoic acid or 2-amino decanoic acid. Preferably, the lipid moiety is attached to the N-and/or C-terminus of the compound. Lipid moieties may e.g. be attached to free N-termini or C-termini of the multimeric compounds. Lipid moieties may also be attached to N- and/or C-terminal linkers, e.g. as described for compounds (Na) and (Mb). In a preferred embodiment of compounds (Ha) and (lib), the C-terminal linkers Y² and Y³ are trifunctional linkers to which a lipid moiety is attached.

The multimeric compounds may further comprise at least one modification, particularly selected from an amide, ester, acyl and/or alkyl moiety attached thereto, e.g. attached to an N-terminal group, a C-terminal group and/or a side chain group. Preferred are N- and/or C-terminal modifications.

A further preferred embodiment is the attachment of acyl, e.g. acetyl groups to the N-termini and/or the amidation of free C-termini.

The compounds of the present invention may have antimicrobial activity, particularly activity against pathogenic organisms selected from prokaryotic organisms, e.g. eubacteria or archaea, and eukaryotic organisms, e.g. fungi, algae or parasites. Preferably, the compounds have antibacterial activity, e.g. activity against Gram-negative and/or Gram-positive bacteria.

A further subject-matter of the present invention is a composition for medical use comprising at least one compound as defined above, e.g. a peptidic or multimeric compound as defined above, together with pharmaceutically acceptable carriers, diluents and/or adjuvants. For use in human or veterinary medicine, the composition is preferably in form of a pharmaceutical dosage form selected from solids, liquids or gels and combinations thereof, e.g. as an eyewash, mouthwash, ointment, aerosol or topical product. The pharmaceutical dosage form comprises an amount of the active agent which is effective for the treatment and/or prevention of disorders caused by, associated with or accompanied by the presence of pathogenic organisms. The actual amount of the active agent may vary depending on the administration route and the type and severity of disorder to be treated.

Still a further embodiment of the present invention refers to a composition for use as a disinfectant and/or detergent comprising at least one compound as described above or for use of a preservative, e.g. a preservative for medical, cosmetic or food products, comprising at least one compound described above.

Further, the present invention shall be explained in more detail by the following examples.

Examples

Materials

Solvents, all of HPLC grade, were obtained from Sigma Aldrich (St. Louis, MO₁ US) and used without further purification. A/,Λ/-diisopropylethylamine (DIEA)₁ piperidine, trifluoroacetic acid and triisopropylsilane were purchased from Aldrich and Fluka (St. Louis, MO, US). Fmoc-aminoacids, HOBT, HBTU and resins were supplied from Chem-lmpex International (Wooddale, III.) and Merck (Darmstadt, Germany).

Peptide Synthesis. All the peptides were synthesised by solid phase synthesis on a MultiSynTech Syro (Witten, Germany), using Fmoc/tBu chemistry. Coupling activation was carried out by HOBt/DIPEA/HBTU (1/2/0.9) in DMF and the Fmoc-protection on amine was removed employing 40% piperidine in NMP. Side chain protecting groups were: te/ϊ-butyl ester for GIu and Asp; trityl for His, GIn and Asn; 2,2,4,6,7-pentamethyldihydro- benzofuran-5-sulfonyl (Pbf) for Arg; terf-butyl ether for Ser, Thr and Tyr; tert- butyloxycarbonyl (Boc) for Lys, Pro and Trp.

Multimeric acid peptides were prepared on lysine core preloaded Wang resin, while multimeric amido peptides on Rink amide NovaPEG, evaluating by spectrophotometric measurements the final loading in free amino groups. Fmoc-Lys(Fmoc)-OH was used to synthesize dimeric and tetrameric peptides. All peptides were cleaved from the resins and deprotected by treatment with trifluoroacetic acid, water and triisopropylsilane (95:2.5:2.5). The crude peptides, obtained by precipitation in diethyl ether, were purified by Waters HPLC-UV (Milford, MA) on a C₁₂ Phenomenex column and characterized by Bruker MALDI-TOF spectrometry (Billerica, Massachusetts).

Determination of MIC. MICs were determined in MHB by the broth microdilution methodology, according to CLSI procedure (formerly NCCLS, Ref. 10) by using final bacterial inocula of 1-5x10⁵ CFU/mL. Assays were performed in sterile 96-well microtiter plates with round bottom wells (Corning Costar). Plates were incubated at 37°C and read after 20-24 h. MIC was defined as the lowest drug concentration causing complete suppression of visible bacterial growth. All compounds were dissolved in (5% v/v DMSO).

Results

It was found that the addition of lipd moieties such as β-alanine (β-Ala), 5- amino valeroic acid (5-Ava), 8-amino octanoic acid (8-Aoa) or 2-amino- decanoic acid (2-Ada) increases the antimicrobial activity of multimeric peptides. A schematic illustration of preferred lipidated multimeric peptidic compounds of the present invention are shown in Figure 1.

In Table 1, the activities of all peptides against the Gram-negative strains E.coli ATCC 25922, Pseudomonas aeruginosa ATCC 27853 and Klebsiella pneumoniae ATCC 10031 and against the Gram-positive strain Staphylococcus aureus ATCC 25923 are listed.

Table 1.

Discussion

The present invention relates to novel antimicrobial lipidated multimeric peptides particularly active against Gram-negative bacteria.

BIBLIOGRAPHY

1. J.N. Chin, MJ. Rybak, CM. Cheung, and P. B. Savage, "Antimicrobial Activities of Ceragenins against Clinical Isolates of Resistant Staphylococcus aureus" (2007), Antimicrobial Agents and Chemotherapy,

51 (4): 1268-1273

2. YJ. Gordon and E.G. Romanowski, "A Review of Antimicrobial Peptides and Their Therapeutic Potential as Anti- Infective Drugs" (2005), Current Eye Res., 30 (7): 505-515. 3. I. S. Radzishevsky, S. Rotem, D. Bourdetsky, S. Navon-Venezia, Y. Carmeli, A. Mor, "Improved antimicrobial peptides based on acyl-lysine oligomers" (2007), Nature Biotechnology, 25: 657-659

4. A.K Marra, WJ. Gooderhama and R.E.W. Hancock, "Antibacterial peptides for therapeutic use: obstacles and realistic outlook" (2006), Current Opinion in Pharmacology, 6 (5): 468-472.

5. R.E.W. Hancock and R.I. Lehrer, "Cationic peptides: a new source of antibiotics" (1998), Trends in Biotechnology, 16 (2): 82-88

6. R.I. Lehrer and T. Ganz, "Antimicrobial peptides in mammalian and insect host defence" (1999), Current Opinion in Immunology, 11 : 23-27 7. K. Radek and R. GaIIo; "Antimicrobial peptides: natural effectors of the innate immune system" (2007), Seminars in Immunopathology, 29 (1 ): 27-43

8. M. G. Scott, H. Yan, and R.E.W. Hancock, "Biological properties of structurally related α-helical cationic antimicrobial peptides" (1999), Infections and Immunity, 67(4): 2005-2009

9. U.H.N. Dϋrra, U.S. Sudheendraa and A. Ramamoorthy, "LL-37, the only human member of the cathelicidin family of antimicrobial peptides" (2006), Biochimica et Biophysica Acta- Biomembranes, 1758 (9): 1408-1425 10. National Committee for Clinical Laboratory Standards. Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically; Approved Standard - Seventh Edition - 2006 - NCCLS document M7-A7, NCCLS, Wayne, PA. 2006.

Claims

1. A multimeric lipidated compound comprising a plurality of antimicrobially active monomeric peptidic units connected via linkers, having a functionality of at least 2, wherein at least one lipid moiety is attached to the N- and/or C-termini of the compound, wherein the peptidic units may comprise D- and/or L-amino acid building blocks.

2. The multimeric lipidated compound according to claim 1 , comprising at least 3, and preferably 4-8 anti-microbially active monomeric peptidic units.

3. The multimeric lipidated compound according to claims 1 or 2 having a branched structure, particularly a dendritic structure.

4. The multimeric lipidated compound according to claim 3 having a dendritic structure represented by the general formula (Ha) or (lib):

[[(AO)M R]n2 Y¹]n3 YMAoJn₅ (Ha)

{[(Ao)m R]n2 Y¹]n3 Y^2'}n4 Y³ (Ao)_nS (lib)

wherein A₀ is a lipid moiety,

5. The multimeric lipidated compound according to claim 4, wherein Y¹ and Y² are trifunctional linkers, e.g. a trifunctional amino acid such as lysine, ornithine, nor-lysine, aminoalanine, aspartic acid or glutamic acid.

6. The multimeric lipidated compound according to claims 4 or 5, wherein in formula (Ha) n2 and n3 are 2, and in formula (lib) n2, n3 and n4 are 2.

7. The multimeric lipidated compound according to any one of claims 1-6, wherein the antimicrobially active peptidic compound has a length of 6-40 and preferably 8-35 amino acid building blocks, which may be selected from amino carboxylic acids, particularly α-amino carboxylic acids, e.g. L-α-amino carboxylic acids, D-α-amino carboxylic acids, genetically encoded α-amino carboxylic acids or non-genetically encoded α-amino carboxylic acids.

8. The multimeric lipidated compound according to any one of claims 1-7, wherein the lipid moiety comprises at least one amino carboxylic acid comprising a linear or cyclic, saturated mono- or polyunsaturated hydrocarbon group having 3 to 25 C-atoms, preferably 5-25 C-atoms, e.g. 5-amino valeroic acid, 8-amino octanoic acid or 2-amino decanoic acid.

9. The multimeric lipidated compound according to any one of claims 1-8 comprising further N- and/or C-terminal modifications, particularly selected from amidation, esterification, acylation and/or alkylation.

10. The multimeric lipidated compound according to any one of claims 1-9, wherein the antimicrobially active peptidic compound comprises the amino acid sequence (Ia):

A₁-[K]_n-K-I-R-V-R (SEQ ID NO: 31 ) wherein Ai ist the N-terminal group, and n is 1 or 0.

11. The compound of any one of claims 1-10 having activity against pathogenic organisms selected from prokaryotic organisms, e.g. eubacteria or archaea, and eukaryotic organisms, e.g. fungi, algae or parasites.

12. The compound of any one of claims 1-11 having anti-bacterial activity.

13. A composition for medical use comprising at least one compound as defined in any one of claims 1-12 together with pharmaceutically acceptable carriers, diluents and/or adjuvants.

14. The composition of claim 13 in form of a pharmaceutical dosage form, selected from solids, liquids, gels and combinations thereof, e.g. as an eyewash, mouthwash, ointment, aerosol or topical product.

15. A composition for use as a disinfectant and/or detergent comprising at least one compound as defined in any one of claims 1-12.

16. A composition for use as a preservative comprising at least one compound as defined in any one of claims 1-12.

17. The compound of claim 16 as a preservative for medical, cosmetic or food products.