WO2009139635A1 - Dérivés de polymyxine et leurs utilisations - Google Patents

Dérivés de polymyxine et leurs utilisations Download PDF

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Publication number
WO2009139635A1
WO2009139635A1 PCT/NL2009/050263 NL2009050263W WO2009139635A1 WO 2009139635 A1 WO2009139635 A1 WO 2009139635A1 NL 2009050263 W NL2009050263 W NL 2009050263W WO 2009139635 A1 WO2009139635 A1 WO 2009139635A1
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Prior art keywords
antibiotic
sensitizer
amino acid
formula
compound
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PCT/NL2009/050263
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English (en)
Inventor
Peter Christian De Visser
Gerard Johannes Platenburg
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Prosensa Technologies B.V.
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Publication of WO2009139635A1 publication Critical patent/WO2009139635A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/04—Linear peptides containing only normal peptide links
    • C07K7/06—Linear peptides containing only normal peptide links having 5 to 11 amino acids

Definitions

  • the present invention is in the field of antimicrobial compositions, in particular in the field of antimicrobial compositions comprising an antibiotic and a compound that acts as an enhancer of the antimicrobial effect of the antibiotic.
  • the invention is particularly useful in combating bacterial strains that are resistant to antibiotics.
  • the bacterial cell wall is a feature where particular antibiotic resistance originates, as it prevents many antibiotics from reaching their targets inside the cell, and may contain antibiotic efflux pump systems. Furthermore, bacteria may produce antibiotic hydrolyzing proteins (e.g. ⁇ -lactamases) that inactivate antibiotics. It is generally believed that if the bacterial membrane could only be rendered more permeable, the effect of antibiotics would be enhanced.
  • antibiotic hydrolyzing proteins e.g. ⁇ -lactamases
  • polymyxins have been reported to cause toxicity during in -human use, especially renal toxicity (see for example Evans, M. E. et al, Ann. Pharmacother. 1999, 33, 960; its contents herein incorporated by reference). This can be attributed to the fact that the fatty acid moiety in polymyxins causes complexation and retention in renal tubes. Moreover, the fact that the body is unable to degrade the cyclic peptide moiety due to both the polyamide character and the presence of unnatural 1,4-diaminobutyric acid (Dab) residues contributes to its toxicity. Although deacylation of polymyxins has a dramatic impact on their antimicrobial activities, toxicity associated with the fatty acid moiety is decreased; still, the remaining cyclic peptide moiety is hard to process by the (human) body.
  • Dab 1,4-diaminobutyric acid
  • antimicrobial sensitizers such as deacylated polymyxin analogues, which may be applied in low amounts, are less toxic and readily available.
  • a combination of such a sensitizer and an antibiotic is capable of rendering microorganisms, preferably bacteria, susceptible to the antibiotic, whereas the antibiotic without the disulfide ring-closed deacylated polymyxin analogue was much less or not at all active against the microorganisms.
  • deacylated polymyxin derivatives in which the ring structure is closed by a disulfide bridge rather than an amide bond, display similar enhancing activity as the amide-bond ring-closed compounds derived from natural polymyxins.
  • the introduction of the disulfide bridge presents two major advantages. Firstly, it is easier to produce, in high yields. Ring closure by disulfide bond formation avoids the need for intricate protection/cyclisation strategies. Secondly, the introduction of a reduction- sensitive bond inside the ring structure facilitates its degradation in the body, thus rendering the deacylated polymyxin derivate less toxic than its known counterparts.
  • a disulfide bridged polymyxin derivative according to the present invention may be referred to as an "antibiotic sensitizer", a well-known concept in the field of antibiotics.
  • the disulfide -bridged polymyxin analogues of the present invention may optionally comprise two amino acids different from that of the polymyxin group yielding polymyxin analogues.
  • the dipeptide can also be replaced by a dipeptide isostere, including but not limited to, turn mimetics. One may thus reduce toxicity and/or promote sensitizing activity any further.
  • Dab represents a 1,4-diaminobutyric acid residue
  • Cys represents a cysteine residue
  • X represents a hydrophobic D-amino acid
  • Y represents a hydrophobic L-amino acid, threonine or serine, or alternatively, X and Y together represent a dipeptide isostere which may include a turn mimetic
  • R 1 represents a hydrogen atom, an alkyl group (preferably having a backbone containing 1-6 atoms, excluding hydrogen), an amino acid, or a dipeptide;
  • R 2 represents H, NH 2 , NHR 3 , (NR 3 ) 2 , R 3 , OH or OR 3 , wherein R 3 is an alkyl group (preferably having 1-6 atoms, excluding hydrogen), an amino acid, or a dipeptide.
  • a turn mimetic is construed to mimic the conformation of the amino acids X-Y in formula (I).
  • the amino acids X and Y, independently, or dipeptide X-Y may be either of natural or of synthetic origin.
  • Hydrophobic amino acids include, but are not limited to alanine, proline, tryptophane, leucine, isoleucine, norleucine, 4-bromophenylalanine, methionine, cyclohexylalanine, phenylglycine, phenylalanine, homophenylalanine, homoleucine, homoisoleucine, naphthylalanine, pyrenylalanine, 2-aminotetradecanoic acid and the like.
  • the hydrophobic amino acid is selected from the above group.
  • the choices for X and Y can further reduce toxicity, compared to their natural polymyxin counterparts.
  • the degree of hydrophobicity of X and Y, or even the choice for threonine or serine, affects the membrane activity of the sensitizer and thus potency and/or toxicity.
  • R 1 and R 3 in formula I can represent, independent of each other, a linear or branched alkyl group comprising at most 6 atoms connected to one another, forming a backbone, excluding hydrogen atoms.
  • alkyl group means that it is a group containing carbon atoms. It is understood that if not specified otherwise, C, O, N and S atoms in the alkyl group further comprise hydrogen atoms to properly satisfy the valency of the respective atom.
  • the definition distinguishes from the hydrophobic fatty acid chain of conventional polymyxin antibiotics.
  • a backbone of at most 6 atoms can be part of a cyclic element, including aromatic rings, in R 1 .
  • the alkyl group may comprise one or more O, N and/or S atoms, which means that the chain of carbon atoms may be interrupted by one or more O, N and/or S atoms.
  • the definition of alkyl in this paragraph includes heteroalkyl.
  • the heteroatoms contribute to the preferred maximum number of atoms.
  • the R 1 and R 3 alkyl groups may comprise one or more double bonds or one or more triple bonds or combinations of double and triple bonds and/or cycloalkyl and/or aryl rings.
  • the at most 6 atoms-containing chain of R 1 and/or R 3 may be interrupted by one or more O, N and/or S atoms, yielding e.g. alkoxyalkyl, alkylthioalkyl, hydroxyalkyl, thioalkyl, aminoalkyl moieties and the like. These heteroatoms sum up to the total number of a maximum of 6 atoms in the backbone.
  • the at most 6 atoms-containing chain of R 1 and/or R 3 may be substituted, for example by one or more halogen atoms and/or groups via one or more O, N and/or S atoms, e.g. hydroxyl, amine and/or thiol groups or O-, N- and/or S-lower (carboxy)alkyl or doubly bound O, N(-H or -alkyl) and/or S.
  • R 1 and R 2 can, independent of each other, also represent an amino acid, including but not limited to racemic, R-, and S-amino acids, ⁇ -, ⁇ -, ⁇ -, and ⁇ -amino acids, dipeptides thereof, and dipeptide isosteres and/or dipeptide mimetics.
  • R 1 is a hydrogen atom or an amino acid residue and R 2 is NH 2 .
  • X is a hydrophobic D-amino acid residue and Y is a hydrophobic L-amino acid residue or L-threonine or L-serine.
  • hydrophobic amino acid residues include, but are not limited to e.g. alanine, proline, tryptophane, leucine, isoleucine, norleucine, 4-bromophenylalanine, methionine, cyclohexylalanine, phenylglycine, phenylalanine, homophenylalanine, homoleucine, homoisoleucine, naphthylalanine, pyrenylalanine, 2-aminotetradecanoic acid and the like.
  • the sensitizer of formula I is present in the form of a salt, in particular an acid addition salt, e.g. its HCl, HBr, HF, H 3 PO 4 , H 2 SO 4> citric acid, acetic acid, trifluoroacetic acid, lactic acid, isethionic acid, maleic acid, methanesulfonic acid or ethylenediamine tetraacetic acid addition salt.
  • an acid addition salt e.g. its HCl, HBr, HF, H 3 PO 4 , H 2 SO 4> citric acid, acetic acid, trifluoroacetic acid, lactic acid, isethionic acid, maleic acid, methanesulfonic acid or ethylenediamine tetraacetic acid addition salt.
  • the invention also pertains to the above compound for use in a medicament.
  • the invention pertains to a composition
  • a composition comprising (i) the compound as defined above, and (ii) an antibiotic, for use in inhibiting microbial bacterial growth.
  • antibiotic encompasses the use of multiple antibiotics, which may be applied for treating the same or different microorganisms.
  • the invention pertains to the above composition, wherein said compound acts as a sensitizer, meaning that it renders microorganisms, in particular bacteria, susceptible to the action of the antibiotic or that it renders said microorganisms susceptible to the action of the antibiotic at a lower concentration or dosage of the antibiotic.
  • the compound of the invention will be referred addressed to as “the antibiotic sensitizer”, thus referring to its use. It is not excluded that the compounds presently contemplated also exhibit antimicrobial activities themselves, without the presence of an antibiotic, albeit at far higher concentrations than opted for here.
  • the current findings on "antibiotic sensitizing properties”, i.e. the ability to permeabilize the -preferably bacterial- membrane to an antibiotic brings additional advantages, including treating microorganisms having reduced susceptibility to antibiotics, or even microorganisms resistant to certain antibiotics.
  • the compound of formula (I) is an active ingredient in the composition, included to enhance the activity of the antibiotic.
  • inhibiting bacterial growth is understood to comprise the combat of infectious microbial disease, preferably bacterial disease, including treatment, prophylaxis, cytocidal, antimicrobial, preferably antibacterial, bacteriostatic and/or bacteriocidal effects.
  • the sensitizer of formula I is present in an amount that is sufficient to enhance the effectiveness of the antibiotic.
  • an effectiveness of an antibiotic is understood that the addition of the antibiotic to a culture medium inhibits growth of the inoculum such that the number of colony forming units (CFU) with the antibiotic is less than 30%, such as 20%, 15%, 10%, or 5% of the CFU without addition of the antibiotic.
  • the addition of the antibiotic kills the inoculum such that the CFU is less than 70%, such as 60%, 50%, 40%, 30%, 20%, 10%, 5%, 2%, 1%, 0.1%, or 0.01% of the inoculum.
  • the minimum inhibitory concentration (MIC) or/and the minimum microcidal, preferably bactericidal concentration (MBC) of the antibiotic without the sensitizer of formula I according to the present invention is decreased by at least 2-fold by the addition of said sensitizer.
  • the decrease is at least 4-fold, such as 8-fold, 10-fold or even more such as 20-fold, 50-fold or even 100-fold.
  • a person skilled in the art is able, based on routine experimentation, to determine what a suitable concentration of the sensitizer is, taking into account the particular sensitizer, the particular antibiotic and the extent to which enhanced effectiveness of the antibiotic is attained.
  • sensitizer(s) and antibiotic(s) in a certain composition can be done, independently from each other, systemically (such as Lp., s.c, i.m., i.v.) or topically.
  • the sensitizer(s) can be administered before, after, or simultaneously with the antibiotic(s).
  • a person skilled in the art is able to determine the best route of administration and time span between two components to obtain a maximum effect. It is preferred that the maximum time between administration of the first sensitizer and the antibiotic is less than 24 hours or more preferably, less than 10 hours.
  • the amounts of sensitizer need not be high to enhance the effectiveness of the antibiotic(s). It is preferred that the molar ratio of sensitizer(s) of formula I to antibiotic(s) is attractively lower than 500:1, more preferably lower than 100:1, particularly at most 20:1.
  • the present compositions preferably comprise an antimicrobially, or antibiotically, effective amount of an antibiotic. From the above it follows that a skilled person is able, based on routine experimentation, to determine what a suitable concentration of the antibiotic is, taking into account the particular sensitizer, the particular antibiotic and the extent to which enhanced effectiveness of the antibiotic is attained.
  • the amount of sensitizer is at least 2 times, preferably at least 5 times, more preferably at least 10 times lower than its MIC and/or MBC value. In one embodiment, it is preferred that the amount of sensitizer in the composition is at least 10 3 its MIC and/or MBC value.
  • the present composition comprises an antibiotic which is selected from the group consisting of ⁇ -lactams, (e.g. ampicillin, ceftazidime, meropenem), quinolones (e.g. norfloxacin, ciprofloxacin), glycopeptides (e.g. vancomycin), macrolides (e.g. erythromycin), oxazolidinones (e.g. linezolid), peptide antibiotics (e.g. magainin II), lipopeptides (e.g. polymyxins, bacitracin), nitroimidazoles (e.g. metronidazole), ansamycins (e.g.
  • ⁇ -lactams e.g. ampicillin, ceftazidime, meropenem
  • quinolones e.g. norfloxacin, ciprofloxacin
  • glycopeptides e.g. vancomycin
  • macrolides e.
  • rifampin azoles (e.g. fluconazole), D-cycloserine, lincosamides (e.g. clindamycin), mupirocin, streptogramins (e.g. dalfopristin, quinupristin), fosfomycin, aminoglycosides (e.g. gentamicin), sulfonamides (e.g. sulfomethoxazole), trimethoprim, tetracyclines (e.g. tigilcycline), novobiocin, chloramphenicol, platensimycin, monobactams and synthetic derivatives of these antibiotics.
  • azoles e.g. fluconazole
  • D-cycloserine lincosamides (e.g. clindamycin), mupirocin, streptogramins (e.g. dalfopristin, quinupristin), fosfo
  • a (combination of) suitable antibiotic(s) to be used in combination with the sensitizer according to formula I is selected from the group consisting of glycopeptides (preferably vancomycin or teicoplanin), ⁇ -lactams, preferably penicillins, such as amdinocillin, ampicillin, amoxicillin, azlocillin, bacampicillin, benzathine penicillin G, carbenicillin, cloxacillin, cyclacillin, dicloxacillin, flucloxacillin, methicillin, mezlocillin, nafcillin, oxacillin, penicillin G, penicillin V, piperacillin, and ticarcillin; cephalosporins, such as the first generation drugs cefadroxil, cefazolin, cephalexin, cephalothin, cephapirin, and cephradine, the second generation drugs cefaclor, cefamandole, cefonicid, cefor
  • the invention is particularly suitable in case the microorganism is to a large extent resistant to the antibiotic.
  • the skilled person is aware of the meaning of the definition of "resistant”, as can be found in guidelines produced by e.g. the Clinical and Laboratory Standards Institute (CLSI, formerly known as NCCLS) in the US, more in particular Performance Standards for antimicrobial susceptibility testing; 11 th international supplement, NCCLS document MlOO, its contents incorporated by reference.
  • the treatment involves inhibiting growth of a microorganism which is resistant to said antibiotic if it were administered in absence of the compound of the invention.
  • the invention also concerns a composition of a sensitizer of formula I as defined above and an antibiotic together with a pharmaceutical acceptable carrier.
  • a pharmaceutical composition may be in solid, semi-solid, liquid etc. form, which are for internal or external application such as a tablet, capsule, liquor, vapour, ointment, paste, spray etc.
  • Formulation into a suitable form is well known to a person skilled in the art, see e.g., "Remington's Pharmaceutical Sciences” and "Encyclopedia of Pharmaceutical Technology”.
  • the present compositions can be used to eradicate Gram negative and/or Gram positive bacteria from places where they are not desired.
  • the present invention also concerns the use of the present antimicrobial compositions for cleaning or sterilising of objects and areas.
  • the sensitizers of formula I as defined above and (an) antibiotic(s) and optionally further cleaning and/or sterilising agents are combined with a suitable carrier or diluent, for example such as water and/or (an) alcohol.
  • compounds of formula I can be applied as (immobilized) bacterial membrane binders due to their affinity for the Lipid A component in Gram-negative bacterial membranes; this property can be applied in i.a. hemoperfusion cartridges for extracorporeal dialysis in case of bloodstream infections (Shoji, H. Ther. Apher. Dial. 2003, 7, 108), the contents of which herein incorporated by reference.
  • the present invention also concerns the use of sensitizers of formula I as defined above and (an) antibiotic(s) for the preparation of a medicament for the treatment of a bacterial infection.
  • the medicament is used for the treatment of infections by bacteria that are resistant or multi-resistant to certain specific antibiotics.
  • the present composition comprises an antibiotic that is effective against Gram-negative and/or Gram-positive bacteria.
  • Gram-positive and Gram- negative bacteria are differentiated by the Gram stain.
  • a Gram-positive species retains the primary stain (crystal violet) when treated with a decolourising agent (alcohol or acetone) whereas a Gram-negative bacterium loses the primary stain.
  • the staining difference reflects the structural differences in the cell walls of Gram-negative and Gram-positive bacteria.
  • the Gram-positive cell wall consists of a relatively thick peptidoglycan layer and teichoic acids whereas the Gram-negative cell wall consists of a relatively thin peptidoglycan layer, and an outer membrane consisting of a lipid bilayer containing phospholipids, lipopolysaccharide, lipoproteins and proteins.
  • the present composition comprises an antibiotic that is effective against Gram-negative bacteria. It may be used for the treatment of infections by Escherichia spp, in particular E. coli, Haemophilus spp, in particular H. influenzae, Pseudomonas spp, in particular P. aeruginosa, Klebsiella, in particular K.
  • spp in particular Helicobacter pylori, Shigella spp, Salmonella spp, Yersinia spp, Campylobacter spp, Neisseria spp, Bordetella spp, Aeromonas spp, Burkholderia spp, Serratia spp, Vibrio spp, Proteus mirabilis, and Acinetobacter spp, in particular A baumannii.
  • the present composition comprises an antibiotic that is effective against Gram-positive bacteria. It may be used for the treatment of infection by Gram- positive bacteria. In one embodiment it is used for the treatment of infections by Staphylococcus spp, in particular methicillin-resistant Staphylococcus aureus, Streptococcus spp, Enterococcus spp, Listeria spp, Staphylococcus spp, Streptococcus spp, Clostridium spp, Bacillus spp, Enterococcus spp, Corynebacterium spp, Legionella spp, Mycobacterium spp,
  • the present invention also concerns the use of sensitizers of formula I as defined above and (an) antibiotic(s) for the preparation of a medicament for the treatment of a microbial, preferably bacterial infection, preferably in human beings, particularly to enhance the antimicrobial activity of the antibiotic(s).
  • the present invention also provides a method for treating microbial, preferably bacterial infections in a patient in need thereof, preferably a human being, the method comprising administering the composition of the invention to the patient.
  • kits of parts comprising: a) at least one sensitizer represented by formula I; and b) at least one antibiotic, intended for the treatment of a microbial, preferably bacterial infection, particularly to enhance the antimicrobial effect of the antibiotic.
  • the sensitizer and the antibiotic may comprise one or more additional features as defined above.
  • the kit of parts is intended for sequential or simultaneous administration, wherein the administration routes for the sensitizer and the antibiotic may be the same or different. Therein, it is preferred to adapt the amount of sensitizer administered to enhance the effectiveness of the antibiotic. Means for achieving this are described above. In case of sequential administration, it is preferred that the time between administration of the sensitizer and the antibiotic(s) is less than 300 minutes.
  • the invention also pertains to the use of compounds of the present invention, as defined by formula I, for enhancing the uptake of oligonucleotides in micro-organism cells, preferably bacterial cells, including, but not limited to, antisense oligonucleotides (phosphates, phosphorothioates, 2'-O-substitued RNA, morpholino, PNA, etc.).
  • antisense oligonucleotides phosphates, phosphorothioates, 2'-O-substitued RNA, morpholino, PNA, etc.
  • the peptide was cleaved from the resin with TFA/TIS/H 2 O 95/2.5/2.5 (v/v/v), with concomitant removal of all protecting groups. Precipitation in cold Et 2 O and decantation yielded the crude peptide. Formation of the disulfide bridge was performed by dissolving the crude peptide in 10OmM aq. NH 4 HCO 3 of which the pH was brought to 10 with 29% NH 4 OH. After 18h, the mixture was concentrated, dissolved in TFA and precipitated in cold Et 2 O. Decantation and drying yielded the crude cyclic peptide that was subsequently purified by reverse- phase HPLC and analysed by MS: calculated [M+H] + 984.2, observed [M+H] + 984.6 for peptide PV3475.
  • the volume in the wells was adjusted to 200 ⁇ L with 20% LB, 100% LB, or 100% MH depending of the assay.
  • medium, bacteria+medium, bacteria+antibiotic, and bacteria+medium+antibiotic were included.
  • the 96-well plate was covered (not airtight) and incubated at 37 0 C while shaking for 18h in a BioTek plate reader; OD 550 was determined at least every lOmin.
  • a MIC value for a specific compound was determined as the lowest concentration at which, after 20h incubation, the OD 550 value was comparable to that of the blank used. It should be noted that in this respect, delay in growth caused by sensitizer/antibiotic combinations were not taken into account, although these observations were made usually one or two concentration steps higher than the reported MIC values in the Tables (vide infra).
  • PV3475 rendered P. aeruginosa PAOl vulnerable to ampicillin, an antibiotic against which PAOl is naturally resistant - which is reflected in the high MIC value of 200 ⁇ g/mL. Growth of PAOl was inhibited in the presence of a combination of 50 ⁇ g/mL ampicillin and a range of 40-0.3 l ⁇ M PV3475. the MIC value of this combination was found at 5 ⁇ M PV3475.
  • PV3475 being inactive itself at concentrations >40 ⁇ M (highest concentration assayed), lowers the MIC value of ampicillin to ⁇ 0.5 ⁇ g/mL from >32 ⁇ g/mL (highest concentration assayed) without sensitizer.
  • MRSA methicillin-resistant Staphylococcus aureus
  • VRE vancomycin-resistant Enterococcus faecalis
  • VRE vancomycin-resistant Enterococcus faecalis
  • lower antibiotic dosages were found to be necessary for inhibiting growth of Staphylococcus spp, Streptococcus spp, Clostridium spp, Bacillus spp, Enterococcus spp, Corynebacterium spp, Legionella spp, Mycobacterium spp, Listeria spp in presence of sensitizers of formula I.

Abstract

La présente invention porte sur des sensibilisants et sur des compositions antimicrobiennes renfermant un antibiotique et un sensibilisant qui augmente l'efficacité ou l'activité de l'antibiotique, le sensibilisant étant de préférence un analogue cyclisé disulfure d'un nonapeptide de polymyxine. L'analogue cyclisé disulfure est caractérisé par : où X représente un acide aminé D hydrophobe naturel ou non naturel ; Y représente un acide aminé L hydrophobe naturel ou non naturel, la thréonine ou la sérine ou, dans une variante, où X et Y représentent ensemble un isostère dipeptidique ou un mimétique de turn ; R1 représente un atome d'hydrogène, un groupe alkyle, un acide aminé ou un dipeptide ; et R2 représente H, NH2, NHR3, (NR3)2, R3, OH ou OR3, où R3 est un groupe alkyle, un acide aminé ou un dipeptide. Les compositions contenant le sensibilisant de l'invention sont particulièrement utiles pour le traitement d'infections par des bactéries résistantes aux médicaments.
PCT/NL2009/050263 2008-05-15 2009-05-15 Dérivés de polymyxine et leurs utilisations WO2009139635A1 (fr)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9790527B2 (en) 2012-05-08 2017-10-17 Codexis, Inc. Engineered proline hydroxylase polypeptides
EP3240794A4 (fr) * 2014-12-31 2018-10-31 Oregon State University Composés antibactériens antisens et procédés associés
CN111247162A (zh) * 2017-10-31 2020-06-05 正大天晴药业集团股份有限公司 多黏菌素类似物及其制备方法

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
CLAUSELL E.A.: "Gram-negative outer and inner membrane models: insertion of cyclic cationic lipopeptides", J.PHYS.CHEM.B, vol. 111, 2007, pages 551 - 563, XP002496861 *
MARTTI VAARA ET AL: "Group of Peptides That Act Synergistically with Hydrophobic Antibiotics against Gram-Negative Enteric Bacteria", ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, AMERICAN SOCIETY FOR MICROBIOLOGY, WASHINGTON, DC, US, vol. 8, no. 40, 1 January 1996 (1996-01-01), pages 1801 - 5, XP002080197, ISSN: 0066-4804 *
TSUBERY H ET AL: "Structure-function studies of polymyxin B nonapeptide: implications to sensitization of gram-negative bacteria", JOURNAL OF MEDICINAL CHEMISTRY, US AMERICAN CHEMICAL SOCIETY. WASHINGTON, vol. 43, no. 16, 10 August 2000 (2000-08-10), pages 3085 - 3092, XP002218257, ISSN: 0022-2623 *
VISSER DE P C ET AL: "Solid-phase synthesis of polymyxin B1 and analogues via a safety-catch approach", JOURNAL OF PEPTIDE RESEARCH, BLACKWELL PUBLISHING LTD., OXFORD, GB, vol. 61, no. 6, 1 June 2003 (2003-06-01), pages 298 - 306, XP002389978, ISSN: 1397-002X *

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9790527B2 (en) 2012-05-08 2017-10-17 Codexis, Inc. Engineered proline hydroxylase polypeptides
EP3240794A4 (fr) * 2014-12-31 2018-10-31 Oregon State University Composés antibactériens antisens et procédés associés
US11293024B2 (en) 2014-12-31 2022-04-05 Board Of Regents, The University Of Texas System Antisense antibacterial compounds and methods
CN111247162A (zh) * 2017-10-31 2020-06-05 正大天晴药业集团股份有限公司 多黏菌素类似物及其制备方法
CN111247162B (zh) * 2017-10-31 2022-02-18 正大天晴药业集团股份有限公司 多黏菌素类似物及其制备方法

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