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WO2010130007A1 - Composés antimicrobiens - Google Patents

Composés antimicrobiens Download PDF

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Publication number
WO2010130007A1
WO2010130007A1 PCT/AU2010/000568 AU2010000568W WO2010130007A1 WO 2010130007 A1 WO2010130007 A1 WO 2010130007A1 AU 2010000568 W AU2010000568 W AU 2010000568W WO 2010130007 A1 WO2010130007 A1 WO 2010130007A1
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WO
WIPO (PCT)
Prior art keywords
alkyl
group
acid
pharmaceutically acceptable
peptide
Prior art date
Application number
PCT/AU2010/000568
Other languages
English (en)
Inventor
Jian Li
Tony Velkov
Roger L Nation
Philip Evan Thompson
Original Assignee
Monash University
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Publication date
Application filed by Monash University filed Critical Monash University
Publication of WO2010130007A1 publication Critical patent/WO2010130007A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/50—Cyclic peptides containing at least one abnormal peptide link
    • C07K7/54—Cyclic peptides containing at least one abnormal peptide link with at least one abnormal peptide link in the ring
    • C07K7/60—Cyclic peptides containing at least one abnormal peptide link with at least one abnormal peptide link in the ring the cyclisation occurring through the 4-amino group of 2,4-diamino-butanoic acid
    • C07K7/62—Polymyxins; Related peptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the present invention relates to antimicrobial compounds and their uses, and in particular to peptide antibiotics which may be used in the treatment of Gram-negative bacterial infections, particularly those caused by multidrug-resistant (MDR) Gram-negative bacteria.
  • MDR multidrug-resistant
  • Gram-negative bacteria Representative genera of Gram-negative bacteria are: Acinetobacter, Actinobacillus; Bartonella; Bordetella; Brucella; Burkholderia; Campylobacter; Cyanobacteria; Enterobacter; Erwinia; Escherichia; Francisella; Helicobacter; Hemophilus; Klebsiella; Legionella; Moraxella; Morganella; Neisseria; Pasteurella; Proteus; Providencia; Pseudomonas; Salmonella; Serratia; Shigella; Stenotrophomonas; Treponema; Vibrio; and Yersinia.
  • IDSA Infectious Diseases Society of America
  • Polymyxins belong to a class of peptides which was discovered more than 50 years ago.
  • the structures of representative polymyxins are shown below:
  • Polymyxins are produced by nonribosomal biosynthetic enzymes from the secondary metabolic pathways of Bacillus pofymyxa. There are two polymyxins clinically available, colistin (polymyxin E) and polymyxin B, and cross resistance exists between these two polymyxins. Despite the efficacy of polymyxins in treating certain Gram-negative bacterial infections, it has been shown that parenteral administration of colistin and polymyxin B can be potentially nephrotoxic and/or neurotoxic. Polymyxins are now being used as last- line antibiotics in patients where all other available antibiotics are inactive.
  • the present invention provides a peptide of formula (I):
  • R 1 is a lipophilic group selected from the group consisting of C 3-22 alkyl, C 3 _ 22 alkenyl, C 6- 16 aryl, C 3-12 cycloalkyl, C 6-16 arylC 1 . 22 alkyl, C 6 - 16 arylC 2-22 alkenyl, C 3 . 12 cycloalkylC 1-22 alkyl and C 3-1 2cycloalkylC 2- 22alkenyl;
  • n and p are each independently 0 or 1 ;
  • R 3 , R 4 and R 5 where present and R 2 , R 6 , R 9 , R 10 and R 11 are each independently selected from the side chain of an amino acid selected from the group consisting of ⁇ , ⁇ - diaminobutyric acid, arginine, histidine, lysine, ornithine, glutamatic acid, glutamate, aspartic acid, aspartate, glutamine, asparagine, serine, threonine and cysteine;
  • X is a residue of the side chain of an amino acid selected from the group consisting of ⁇ , ⁇ - diaminobutyric acid, arginine, histidine, lysine, ornithine, glutamatic acid, glutamate, aspartic acid, aspartate, glutamine, asparagine, serine, threonine and cysteine;
  • R 7 is a lipophilic group selected from the group consisting of C 3-22 alkyl, C 3-22 alkenyl, C 6- 16 aryl, C 3- i 2 cycloalkyl, C 6 . 16 arylC 1-22 alkyl, C 6 . 16 arylC 1-22 alkenyl, C 3 . 12 cycloalkylC 1-22 alkyl and Cs. ⁇ cycloalkylCi ⁇ alkenyl;
  • R 8 is a lipophilic group selected from the group consisting of C 3 - 22 alkyl, C 3-22 alkenyl, C 6- 16 aryl, C 3 . 12 cycloalkyl, C 6-16 arylC 1-22 alkyl, C 6 - 16 arylC 1 . 22 alkenyl, C 3 . 12 cycloalkylC 1-22 alkyl and C 3- j 2 cycloalkylC 1 - 22 alkenyl;
  • any alkyl, alkenyl, aryl and cycloalkyl group within the peptide is optionally substituted with one or more groups selected from the group consisting of Ci -22 alkyl, C 2 - 2 2 alkenyl, C 6 . 16 aryl, Cs- ⁇ cycloalkyl, hydroxy, hydroxyC 1 - 22 alkyl, amino, aminoC 1 - 22 alkyl, C 1-22 alkyloxy, Q ⁇ alkylamino, (C 1-22 alkyl)(C 1-22 alkyl)amino, Ci- 22 alkylcarbonyloxy, C 2 . 2 2 alkenylcarbonyloxy, C 6 .
  • the peptides of the present invention are active against Gram- negative bacteria and surprisingly against not only polymyxin-susceptible but also polymyxin-resistant MDR Gram-negative bacteria. It is believed that increasing the number of carbon atoms in the R 8 group to greater than 4 enhances lipophilicity at that position to an extent that may be sufficient to render the peptide effective against both polymyxin-susceptible and -resistant Gram-negative bacteria.
  • the number of carbon atoms in the R ⁇ group may be greater than 5, greater than 6 or greater than 7.
  • the number of carbon atoms in the R 7 group may be greater than 3, greater than 4, greater than 5 or greater than 6.
  • the combined number of carbon atoms in the R 7 and R 8 groups is greater than 11 and may be greater than 12, greater than 13 or greater than 14.
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a peptide as hereinbefore defined, or a pharmaceutically acceptable salt thereof, together with at least one pharmaceutically acceptable carrier or diluent.
  • the invention provides a method of preventing or treating a bacterial infection comprising the step of administering a therapeutically effective amount of a peptide as hereinbefore described, or a pharmaceutically acceptable salt thereof, to a subject in need thereof.
  • the invention provides a use of a peptide as hereinbefore described, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for the prevention or treatment of a bacterial infection.
  • Figure 1 shows static time-kill of compound 3 and colistin against a colistin-resistant MDR clinical P. aeruginosa isolate D.
  • Figure 2 shows static time-kill of compound 2 and colistin against a colistin-resistant MDR clinical P. aeruginosa isolate D.
  • Figure 3 shows static time-kill of compound 3 and colistin against P. aeruginosa ATCC 27853. Detailed description of the invention
  • LPS lipopolysaccharide
  • OM outer membrane
  • LPS is composed of three domains, a conserved inner core 2-keto-3-deoxyoctonoic acid bound to lipid A and a variable O-antigen composed of repeating units of various polysaccharides.
  • the consensus structure of lipid A consists of a ⁇ -l'-6-linked D- glucosamine disaccharide that is phosphorylated at the 1- and 4' -positions and is shown below:
  • Lipid A usually contains six acyl chains. Four ⁇ -hydroxy acyl chains (usually C 10 and C 12 in length) are attached directly to the glucosamine sugars, while a secondary acyl chain is often attached to the ⁇ -hydroxy group on each of two of the chains. Lipid A acts as a hydrophobic anchor with the tight packing of the fatty acyl chains helping to stabilise the overall membrane structure.
  • aeruginosa modification of one or both of the phosphates of lipid A with moieties, such as 4-amino-4-deoxy-L-arabinose (L-Ara4N) and/or phosphoethanolamine (PEtn), reduces the net negative charge of lipid A thereby reducing the initial interaction of a polymyxin with lipid A leading to polymyxin resistance.
  • moieties such as 4-amino-4-deoxy-L-arabinose (L-Ara4N) and/or phosphoethanolamine (PEtn)
  • MCC Minimum Bactericidal Concentration
  • the peptides of the present invention are not only effective against polymyxin-susceptible but also polymyxin-resistant MDR Gram-negative bacteria. Without wishing to be bound by theory it is believed that sufficient binding between a polymyxin analog and lipid A may be achieved by overcoming, or at least ameliorating, the adverse polar interactions between a modified moiety on the phosphate group of lipid A and the positively charged residues on polymyxins through enhancement of the interactions between the lipophilic groups on lipid A and certain residues on the polymyxin analog.
  • the lipophilic groups R 1 , R 7 and R 8 interact with the acyl chains in lipid A
  • the X, R 2 , R 6 , R 9 , R 10 and R 11 groups and the R 3 , R 4 and R 5 where present, which are generally hydrophilic interact with the polar, charged portions of lipid A.
  • lipid A has undergone glycosylation or modification with phosphoethanolamine as part of the resistance mechanism in the bacteria, it is believed that the lipophilic groups and the generally hydrophilic groups remain able to maintain these same interactions.
  • the peptides of the present invention are effective against not only polymyxin-susceptible but also polymyxin- resistant MDR Gram-negative bacteria.
  • the side chain residue X is the residue of the side chain of ⁇ , ⁇ - diaminobutyric acid (Dab) and the peptide is of formula (II):
  • the linear peptide portion of the molecule comprises three amino acids, as do the naturally occurring polymyxin structures.
  • m and p may be equal to 1 and n may be equal to 0.
  • R 1 and R 8 are lipophilic groups as hereinbefore defined;
  • R 2 is the side chain of ⁇ , ⁇ -diaminobutyric acid or threonine;
  • R 5 is the side chain of ⁇ , ⁇ -diaminobutyric acid, serine or threonine;
  • R 7 is the side chain of leucine or phenylalanine.
  • R 1 and R 8 are lipophilic groups as hereinbefore defined;
  • R 5 is the side chain of ⁇ , ⁇ -diaminobutyric acid or serine; and
  • R 7 is the side chain of leucine or phenylalanine.
  • Each amino acid residue within the peptide may be in the L- or D-form.
  • the absolute stereochemistry at each of the stereocentres in the compound of formula (V) shown below is the same as the corresponding stereochemistry in the naturally occurring polymyxin structures:
  • the absolute stereochemistry of the stereocentres adjacent to the R 7 and R 8 groups respectively have not been defined.
  • the amino acid(s) providing the R 7 and/or R 8 group is/are used as a mixture of enantiomers, such as a racemate
  • the peptide so formed that includes the R 7 and R 8 groups will, in the absence of purification of an intermediate peptide, generally be prepared as a mixture of diastereomers.
  • the peptide may be used as a mixture of diastereomers, such as in the treatment of a bacterial infection.
  • the peptide may be used as a single diastereomer, which may be isolated from a mixture of diastereomers or may be prepared using an enantiopure, or enantioenriched, amino acid(s) that provides the R 7 and/or R 8 group. It is believed that preferred peptides are those in which the stereocentre adjacent to the R 7 group has the stereochemistry of D-phenylalanine - having R stereochemistry and/or where the amino acid is in the D-form. It is believed that preferred peptides are those in which the stereocentre adjacent to the R 8 group has the stereochemistry of naturally occurring amino acids such as L-leucine - having S 1 stereochemistry and/or where the amino acid is in the L-form.
  • the peptide is used as a single diastereomer, it is typically preferable that the peptide is made using an enantiopure, or enantioenriched, amino acid containing the R 7 and/or R 8 group rather than being purified following synthesis using a racemic mixture of the amino acid.
  • Preferred examples of lipophilic groups are as follows:
  • Ri is selected from the group consisting of C 3- ⁇ alkyl, phenyl, bi-phenyl, cyclohexanylbutyl, trans-4-propylcyclohexanyl, cyclododecanyl and cyclopentylphenyl;
  • R 7 is the side chain of leucine or phenylalanine
  • R 8 is selected from the group consisting of Cs-ioalkyl, phenyl, bi-phenyl, cyclohexylbutyl, trans-4-propylcyclohexanyl, cyclododecanyl and cyclopentylphenyl.
  • alkyl used either alone or in compound words denotes straight chain or branched alkyl.
  • the alkyl group is a straight chain alkyl group.
  • Prefixes such as “C 3-22” are used to denote the number of carbon atoms within the alkyl group (from 3 to 22 in this case).
  • straight chain and branched alkyl examples include methyl, ethyl, ⁇ -propyl, isopropyl, «-butyl, sec-butyl, t-butyl, n-pentyl, hexyl, heptyl, 5-methylheptyl, 5- methylhexyl, octyl, nonyl, decyl, undecyl, dodecyl and docosyl (C 22 ).
  • cycloalkyl used either alone or in compound words denotes a cyclic alkyl group. Prefixes such as “C 3-12 " are used to denote the number of carbon atoms within the cyclic portion of the alkyl group (from 3 to 12 in this case).
  • cyclic alkyl include mono- or polycyclic alkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl and cyclododecyl.
  • alkenyl used either alone or in compound words denotes straight chain or branched hydrocarbon residues containing at least one carbon to carbon double bond including ethylenically mono-, di- or polyunsaturated alkyl groups as previously defined.
  • the alkenyl group is a straight chain alkenyl group
  • Prefixes such as “C 3-22” are used to denote the number of carbon atoms within the alkenyl group (from 3 to 22 in this case).
  • alkenyl examples include vinyl, allyl, 1 -methyl vinyl, butenyl, iso-butenyl, 3-methyl-2-butenyl, 1-pentenyl, 1-hexenyl, 3-hexenyl, 1-heptenyl, 3- heptenyl, 1-octenyl, 1-nonenyl, 2-nonenyl, 3-nonenyl, 1-decenyl, 3-decenyl, 1,3- butadienyl, 1 ,4-pentadienyl, 1,3-hexadienyl, 1,4-hexadienyl and 5-docosenyl (C 22 ).
  • aryl denotes any of single, polynuclear, conjugated and fused residues of aromatic hydrocarbon ring systems. Prefixes such as “C 6-16 " are used to denote the number of carbon atoms within the cyclic portion of the aryl group (from 6 to 16 in this case). Examples of aryl include phenyl, naphthyl and tetrahydronaphthyl.
  • lipophilic refers to a property of a chemical compound, or part thereof, wherein the chemical compound or part thereof more readily associates with members of a large and diverse group of oils, fats and fat like substances (that occur, for example, in living organisms) than with water.
  • lipophilic groups are groups which, of themselves, display a preference to be solubilised by lipidic solvents rather than aqueous solvents.
  • side chain As used herein, reference to an amino acid "side chain” takes its standard meaning in the art. Examples of side chains of amino acids are shown below:
  • the peptides of the present invention may exist in one or more stereoisomeric forms (eg enantiomers, diastereomers).
  • the present invention includes within its scope all of these stereoisomeric forms either isolated (in for example enantiomeric isolation), or in combination (including racemic mixtures and diastereomic mixtures).
  • the present invention contemplates the use of amino acids in both L and D forms, including the use of amino acids independently selected from L and D forms. For example, where the peptide comprises two Dab residues, each Dab residue may have the same, or opposite, absolute stereochemistry.
  • R 7 and R 8 appended 2-aminoethanoic acid reagents may be accomplished using known techniques - for example: Wimrner, N., et al. (2002) Syntheses of polycationic dendrimers on lipophilic peptide core for complexation and transport of oligonucleotides, Bioorg. Med. Chem. Lett. 12, 2635-2637; and Gibbons, W. A., et al.
  • lipidic amino acids such as: may be prepared for use in the synthesis of the polymyxin peptide analogs of the present invention.
  • the R 7 and R 8 appended amino acids may be prepared as racemates or, alternatively, the amino acids or synthetic intermediates may be resolved to provide enantiopure, or at least enantioenriched, products. The resolution may take place chemically or enzymatically for example.
  • the amino acids bearing the R 7 and R 8 side chains may be synthesised in enantiopure, or at least enantioenriched, form through stereoselective synthesis and/or purification techniques such as recrystallisation.
  • a number of amino acids bearing lipophilic groups defined by R 7 and/or R 8 in enantiopure, or enantioenriched, form are commercially available. Examples of R 7 appended amino acids that may be used in enantiopure, or at least enantioenriched, form are shown below:
  • R 8 appended amino acids that may be used in enantiopure, or at least enantioenriched, form are shown below:
  • Known solid or solution phase techniques may be used in the synthesis of the peptides of the present invention, such as coupling of the N- or C-terminus to a solid support (typically a resin) followed by step-wise synthesis of the linear peptide.
  • An orthogonal protecting group strategy may be used to facilitate selective deprotection and cyclization to form the cyclic heptapeptide core of the peptide.
  • Protecting group chemistries for the protection of amino acid residues, including side chains, are well known in the art and may be found for example in: Theodora W. Greene and Peter G. M. Wuts, Protecting Groups in Organic Synthesis, (Third Edition, John Wiley & Sons, Inc, 1999) - the entire contents of which is incorporated herein by reference.
  • the synthesis of the peptides of the present invention may be performed in four stages.
  • amino acids may be protected for incorporation into the peptide (such as the protection of biphenylglycine as Fmoc-biphenylglycine).
  • a partially protected linear peptide which selectively exposes only the functional groups required for cyclization may be synthesised using solid phase techniques.
  • the cyclization reaction may be performed in solution to produce the protected cyclic lipopeptide.
  • Fourth the remaining side chain protecting groups may be deprotected to furnish the peptide.
  • chromatographic techniques such as high-performance liquid chromatography (HPLC) and reversed-phase HPLC may be used.
  • HPLC high-performance liquid chromatography
  • the peptides may be characterised by mass spectrometry and/or other appropriate methods.
  • the peptide comprises one or more functional groups that may be protonated or deprotonated (for example at physiological pH) the peptide may be prepared and/or isolated as a pharmaceutically acceptable salt. It will be appreciated that the peptide may be zwitterionic at a given pH.
  • pharmaceutically acceptable salt refers to the salt of a given compound, wherein the salt is suitable for administration as a pharmaceutical. For example, such salts may be formed by the reaction of an acid or a base with an amine or a carboxylic acid group respectively.
  • Pharmaceutically acceptable acid addition salts may be prepared from inorganic and organic acids.
  • inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like.
  • organic acids include acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid and the like.
  • Pharmaceutically acceptable base addition salts may be prepared from inorganic and organic bases.
  • Corresponding counterions derived from inorganic bases include the sodium, potassium, lithium, ammonium;, calcium and magnesium salts.
  • Organic bases include primary, secondary and tertiary amines, substituted amines including naturally- occurring substituted amines, and cyclic amines, including isopropylamine, trimethyl amine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2- dimethylaminoethanol, tromethamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, N-alkylglucamines, theobromine, purines, piperazine, piperidine, and N-ethylpiperidine.
  • Acid/base addition salts tend to be more soluble in aqueous solvents than the corresponding free acid/base forms.
  • the compounds of the invention may be in crystalline form or as solvates (e.g. hydrates) and it is intended that both forms are within the scope of the present invention.
  • solvate is a complex of variable stoichiometry formed by a solute (in this invention, a peptide of the invention) and a solvent. Such solvents should not interfere with the biological activity of the solute. Solvents may be, by way of example, water, ethanol or acetic acid. Methods of solvation are generally known within the art.
  • the compounds of the invention may be in the form of a "pro-drug".
  • pro-drug is used in its broadest sense and encompasses those derivatives that are converted in vivo to the peptides of the invention. Such derivatives would readily occur to those skilled in the art and include, for example, compounds where a free hydroxy group is converted into an ester derivative or a ring nitrogen atom is converted to an N-oxide. Examples of ester derivatives include alkyl esters (for example acetates, lactates and glutamines), phosphate esters and those formed from amino acids (for example valine). Any compound that is a prodrug of a peptide of the invention is within the scope and spirit of the invention. Conventional procedures for the preparation of suitable prodrugs according to the invention are described in text books, such as "Design of Prodrugs" Ed. H. Bundgaard, Elsevier, 1985 - the entire contents of which is incorporated herein by reference.
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a peptide as hereinbefore defined, or a pharmaceutically acceptable salt thereof, together with at least one pharmaceutically acceptable carrier or diluent.
  • composition is intended to include the formulation of an active ingredient with encapsulating material as carrier, to give a capsule in which the active ingredient (with or without other carrier) is surrounded by carriers.
  • the peptide as hereinbefore described, or pharmaceutically acceptable salt thereof may be the sole active ingredient administered to the subject, the administration of other active ingredient(s) with the compound is within the scope of the invention.
  • the compound could be administered with one or more therapeutic agents in combination.
  • the combination may allow for separate, sequential or simultaneous administration of the peptide as hereinbefore described with the other active ingredient(s).
  • the combination may be provided in the form of a pharmaceutical composition.
  • the route of administration and the nature of the pharmaceutically acceptable carrier will depend on the nature of the condition and the mammal to be treated. It is believed that the choice of a particular carrier or delivery system, and route of administration could be readily determined by a person skilled in the art. In the preparation of any formulation containing the peptide actives care should be taken to ensure that the activity of the peptide is not destroyed in the process and that the peptide is able to reach its site of action without being destroyed. In some circumstances it may be necessary to protect the peptide by means known in the art, such as, for example, micro encapsulation. Similarly the route of administration chosen should be such that the peptide reaches its site of action.
  • Those skilled in the art may readily determine appropriate formulations for the peptides of the present invention using conventional approaches. Identification of preferred pH ranges and suitable excipients, for example antioxidants, is routine in the art. Buffer systems are routinely used to provide pH values of a desired range and include carboxylic acid buffers for example acetate, citrate, lactate and succinate. A variety of antioxidants are available for such formulations including phenolic compounds such as BHT or vitamin E, reducing agents such as methionine or sulphite, and metal chelators such as EDTA.
  • phenolic compounds such as BHT or vitamin E
  • reducing agents such as methionine or sulphite
  • metal chelators such as EDTA.
  • the peptide as hereinbefore described, or pharmaceutically acceptable salt thereof may be prepared in parenteral dosage forms, including those suitable for intravenous, intrathecal, and intracerebral or epidural delivery.
  • the pharmaceutical forms suitable for injectable use include sterile injectable solutions or dispersions, and sterile powders for the extemporaneous preparation of sterile injectable solutions. They should be stable under the conditions of manufacture and storage and may be preserved against reduction or oxidation and the contaminating action of microorganisms such as bacteria or fungi.
  • the solvent or dispersion medium for the injectable solution or dispersion may contain any of the conventional solvent or carrier systems for peptide actives, and may contain, for example, water, ethanol, polyol (for example, glycerol, propylene glycol and liquid polyethylene glycol, and the like), suitable mixtures thereof, and vegetable oils.
  • the proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants.
  • the prevention of the action of microorganisms can be brought about where necessary by the inclusion of various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal and the like. In many cases, it will be preferable to include agents to adjust osmolarity, for example, sugars or sodium chloride.
  • the formulation for injection will be isotonic with blood.
  • Prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminium nionostearate and gelatin.
  • Pharmaceutical forms suitable for injectable use may be delivered by any appropriate route including intravenous, intramuscular, intracerebral, intrathecal, epidural injection or infusion.
  • Sterile injectable solutions are prepared by incorporating the active peptide in the required amount in the appropriate solvent with various of the other ingredients such as those enumerated above, as required, followed by filtered sterilization.
  • dispersions are prepared by incorporating the various sterilised active ingredient into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above.
  • preferred methods of preparation are vacuum drying or freeze-drying of a previously sterile-filtered solution of the active ingredient plus any additional desired ingredients.
  • compositions include oral and enteral formulations of the present invention, in which the active peptide may be formulated with an inert diluent or with an assimilable edible carrier, or it may be enclosed in hard or soft shell gelatin capsule, or it may be compressed into tablets, or it may be incorporated directly with the food of the diet.
  • the active peptide may be incorporated with excipients and used in the form of ingestible tablets, buccal or sublingual tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like. It will be appreciated that some of these oral formulation types, such as buccal and sublingual tablets, have the potential to avoid liver metabolism. However the peptides of the present invention may also be delivered to the stomach where liver metabolism is likely to be involved. The amount of active peptide in such therapeutically useful compositions is such that a suitable dosage will be obtained.
  • the tablets, troches, pills, capsules and the like may also contain the components as listed hereafter: a binder such as gum, acacia, corn starch or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid and the like; a lubricant such as magnesium stearate; and a sweetening agent such a sucrose, lactose or saccharin may be added or a flavouring agent such as peppermint, oil of wintergreen, or cherry flavouring.
  • a binder such as gum, acacia, corn starch or gelatin
  • excipients such as dicalcium phosphate
  • a disintegrating agent such as corn starch, potato starch, alginic acid and the like
  • a lubricant such as magnesium stearate
  • a sweetening agent such as sucrose, lactose or saccharin may be added or a flavouring agent such as peppermint, oil of winter
  • tablets, pills, or capsules may be coated with shellac, sugar or both.
  • a syrup or elixir may contain the active peptide, sucrose as a sweetening agent, methyl and propylparabens as preservatives, a dye and flavouring such as cherry or orange flavour.
  • any material used in preparing any dosage unit form should be pharmaceutically pure and substantially non-toxic in the amounts employed.
  • the active peptide(s) may be incorporated into sustained-release preparations and formulations, including those that allow specific delivery of the active peptide to specific regions of the gut.
  • Liquid formulations may also be administered enterally via a stomach or oesophageal tube.
  • Enteral formulations may be prepared in the form of suppositories by mixing with appropriate bases, such as emulsifying bases or water-soluble bases. It is also possible, but not necessary, for the peptides of the present invention to be administered topically, intranasally, intravaginally, intraocularly and the like.
  • the present invention also extends to any other forms suitable for administration, for example topical application such as creams, lotions and gels, or compositions suitable for inhalation or intranasal delivery, for example solutions, dry powders, suspensions or emulsions.
  • topical application such as creams, lotions and gels
  • compositions suitable for inhalation or intranasal delivery for example solutions, dry powders, suspensions or emulsions.
  • the peptides of the present invention may be administered by inhalation in the form of an aerosol spray from a pressurised dispenser or container, which contains a propellant such as carbon dioxide gas, dichlorodifluoromethane, nitrogen, propane or other suitable gas or combination of gases.
  • a propellant such as carbon dioxide gas, dichlorodifluoromethane, nitrogen, propane or other suitable gas or combination of gases.
  • the peptides may also be administered using a nebuliser.
  • Pharmaceutically acceptable vehicles and/or diluents include any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like.
  • the use of such media and agents for pharmaceutical active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, use thereof in the therapeutic compositions is contemplated. Supplementary active ingredients can also be incorporated into the compositions.
  • Dosage unit form refers to physically discrete units suited as unitary dosages for the mammalian subjects to be treated; each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect in association with the required pharmaceutically acceptable vehicle.
  • the specification for the novel dosage unit forms of the invention are dictated by and directly dependent on (a) the unique characteristics of the active material and the particular therapeutic effect to be achieved, and (b) the limitations inherent in the art of compounding active materials for the treatment of disease in living subjects having a diseased condition in which bodily health is impaired as herein disclosed in detail.
  • the principal active ingredient may be compounded for convenient and effective administration in therapeutically effective amounts with a suitable pharmaceutically acceptable vehicle in dosage unit form.
  • a unit dosage form can, for example, contain the principal active compound in amounts ranging from 0.25 ⁇ g to about 2000 mg. Expressed in proportions, the active compound may be present in from about 0.25 ⁇ g to about 2000 mg/mL of carrier.
  • the dosages are determined by reference to the usual dose and manner of administration of the said ingredients.
  • therapeutically effective amount refers to that amount which is sufficient to effect treatment, as defined below, when administered to an animal, preferably a mammal, more preferably a human in need of such treatment.
  • the therapeutically effective amount will vary depending on the subject and nature of bacterial infection being treated, the severity of the infection and the manner of administration, and may be determined routinely by one of ordinary skill in the art.
  • treatment and “treating” as used herein cover any treatment of a condition or disease in an animal, preferably a mammal, more preferably a human, and includes: (i) inhibiting the bacterial infection, i.e. arresting its proliferation; (ii) relieving the infection, i.e.
  • prevention and preventing cover the prevention or prophylaxis of a condition or disease in an animal, preferably a mammal, more preferably a human and includes preventing the bacterial infection from occurring in a subject which may be predisposed to infection but has not yet been diagnosed as being infected.
  • the bacterial infection is a Gram-negative bacterial infection.
  • the bacterial infection may be caused by one or more species selected from one or more of the genera Acinetobacter; Actinobacillus; Bartonella; Bordetella; Brucella; Burkholderia; Campylobacter; Cyanobacteria; Enterobacter; Erwinia; Escherichia; Francisella; Helicobacter; Hemophilus; Klebsiella; Legionella; Moraxella; Morganella; Neisseria; Pasteurella; Proteus; Providencia; Pseudomonas; Salmonella; Serratia; Shigella; Stenotrophomonas; Treponema; Vibrio; and Yersinia.
  • Specific examples of species are Pseudomonas aeruginosa, Acinetobacter baumannii, Klebsiella pneumoniae, Escherichia coli and Salmonella enterica.
  • L-2-aminodecanoic acid is available commercially from a number of sources including: www.chemicalbook.com; www.anaspec.com; www.chemexper.com; and www.icis.com.
  • L-2-aminooctanoic acid is available commercially from a number of sources including: www.chemicalbook.com.
  • tBoc t-butoxycarbonyl
  • Synthesis was performed in an automated synthesizer using acid labile Wang resin.
  • the synthesis used 0(6-Chlorobenzotriazol- 1 -yty-N ⁇ iV'.N'-tetramethyluronium hexafluorophosphate (HCTU) or O-(Benzotriazol-l-yl)-N,iV,N',N'-tetramethyluronium tetrafluoroborate (TBTU) as activators.
  • Fmoc deprotection was carried out using 20% piperidine in DMF.
  • the N° acylation was performed for 30 min using a four-fold molar excess of nonanoic acid, a four-fold molar excess of the activator HCTU or TBTU, and an eightfold molar excess of JV-methyl morpholine.
  • the cyclization mixture (consisting of benzotriazole-l-yl-oxy-tris-pyrrolidinophosphonium hexafluorophosphate (PyBop), iV-hydroxybenzotriazole (HOBt), and iV-methyl morpholine (NMM)) at the molar excess of 2-, 2- and 4-fold respectively was added to the peptide (dissolved in DMF) and allowed to react for 2 h.
  • the cyclized, protected peptide was precipitated by the addition of cold diethyl ether.
  • the residual protecting groups were removed by subjecting the peptide (dissolved in acetic acid-methanol-water [5:4:1]) to an atmosphere of hydrogen in the presence of a palladium charcoal catalyst.
  • the deprotected and cyclized peptide was purified by reversed phase chromatography using conventional gradients of acetonitrile:water:trifluoroacetic acid. Compound 1 was dried by lyophilization. The purity was >95% as estimated by reversed-phase HPLC (MALDI- TOF: m/z 1262.3 (100%, M + ), 1284.5 (16%, M+Na + )).
  • Peptide was synthesized by conventional solid phase chemistry, by a standard Fmoc protection strategy.
  • the Dab ⁇ -amino groups were protected by t-butoxycarbonyl (tBoc), and threonine was protected as the t-butyl ether (tBu).
  • the ⁇ -amino group of the Dab residue involved in cyclization was protected by ivDde, which is a hydrazine labile group that can be removed prior to the cleavage step.
  • Synthesis was performed in an automated synthesizer using super acid labile chlorotrityl resin.
  • the synthesis used 0-(6-Chlorobenzotriazol-l-yl)-iV ) N ) N',N'-tetramethyluronium hexafluorophosphate (HCTU).
  • Fmoc deprotection was carried out using 20% piperidine in DMF.
  • the Na acylation was performed for 30 min using a four-fold molar excess of octanoic acid, a four-fold molar excess of the activator HCTU, and an eightfold molar excess of iV-diisopropylethylamine.
  • Cleavage of the peptide from the resin was achieved by treating the resin with 2% TFA in dichloromethane or hexafluoroisopropanol or acetic acid in trifluoroethanol.
  • the partially protected linear peptide was isolated by treatment with hexane.
  • the cyclization mixture (consisting of diphenylphosphorylazide, and diisopropylethylamine at the molar excess of 2, and 4-fold respectively) was added to the peptide (dissolved in DMF) and allowed to react for 2 h.
  • the DMF was removed and the cyclized, protected peptide was precipitated by the addition of cold diethyl ether.
  • the residual protecting groups were removed by treating the peptide with 95% TFA:5% water.
  • the deprotected and cyclized peptide was purified by reversed-phase chromatography using conventional gradients of acetonitrile:water:trifluoroacetic acid. Compound 2 was dried by lyophilization. The purity was >95% as estimated by reversed-phase HPLC (MALDI-TOF: m/z 1245.7 (55%, M+), 1267.7 (100%, M+Na + )).
  • MALDI-TOF m/z 1321.6 (100%, M+Na + );
  • MALDI-TOF m/z 1340.4 (29%, M + ), 1362.9 (100%, M+Na + ), 1378.9 (41%);
  • MICs were determined by broth microdilution in cation-adjusted Mueller-Hinton broth (CAMHB, magnesium concentration 10 to 12.5 mg/L, and calcium concentration 20 to 25 mg/L) (Oxoid Australia, Thebarton, SA 5 Australia) according to the Clinical and Laboratory Standards Institute protocol (Clinical and Laboratory Standards Institute. Performance standards for antimicrobial susceptibility testing; eighteenth informational supplement M100-S18. Wayne, PA, 2008). The strains examined were: P.
  • aeruginosa ATCC 27853 and 9 multidrug-resistant strains, including 7 polymyxin-resistant strains (strains A-G)); A, baumannii (ATCC 19606 and 6 multidrug-resistant strains, including 5 polymyxin- resistant strains (strains J-N)) and K. pneumoniae (ATCC 13883 and 5 multidrug-resistant strains, including 4 polymyxin-resistant strains (strains P, R-T)).
  • MICs were measured against P. aeruginosa, A. baumannii and K. pneumoniae.
  • the results for compounds 2 — 5 are shown in Table 1.
  • Viable counting was conducted at the end of the MIC experiments for the wells of MIC, 2 ⁇ MIC and 4x MIC.
  • these compounds usually killed all bacterial cells (detected by viable counting with 50 ⁇ L broth culture) either at the MIC or 2-4x MIC (i.e. MBC) in the MIC experiments, which is in sharp contrast to polymyxins usually requiring 8-32 x MIC to achieve complete bacterial kill.
  • the expressions "100% bacterial killing", "complete bacterial kill” and variants thereof refer to the killing of substantially all of the bacterial cells present as measured by viable counting.
  • the MIC for compound 1 was 5.2-10.3 mg/L against a number of polymyxin-susceptible (P. aeruginosa ATCC 27853, A. baumannii ATCC 19606 and K. pneumoniae B5055AlpxM) and polymyxin-resistant (P. aeruginosa, A. baumannii and K. pneumoniae) bacterial strains.
  • Counting of viable bacteria after 24 h incubation revealed that compound 1 achieved 100% bacterial killing at 10.3 mg/L (the MBC) against both polymyxin- susceptible and polymyxin-resistant A. baumannii.
  • colistin was inactive (even at 128 mg/L) against the resistant strain, and required at least 16 mg/L to achieve complete killing of the susceptible strain.
  • bacterial counting indicated substantial killing of K. pneumoniae and P. aeruginosa by compound 1.
  • the MICs of compound 3 were not affected by calcium concentrations in CAMHB (100 mg/L versus 20 mg/L) against both colistin-resistant and colistin- susceptible P. aeruginosa strains (2 strains for each type were examined).
  • the MIC for colistin against P. aeruginosa ATCC 27853 increased from 1 mg/L (in the presence of 20 mg/L calcium) to 4 mg/L with 100 mg/L calcium. This indicates that much stronger interactions exist between the compounds of the present invention and lipid A, compared to the interaction between colistin and lipid A. This conclusion is consistent with the findings shown in Example 4 below.
  • samples of bacterial cell suspension 50 ⁇ L were spirally plated on nutrient agar plates (Medium Preparation Unit, University of Melbourne) using a Whitley automatic spiral plater (WASP, Don Whitley Scientific, West Yorkshire, UK). Colonies were counted by a ProtoCOL automated colony counter (Synbiosis, Cambridge, UK) after 24 h incubation of subcultures at 35 0 C. The lower limit of counting was 20 CFU/mL.
  • the antibacterial killing kinetics of compounds 3 and 2 a gainst two colistin-resistant (colistin MICs > 128 mg/L) MDR clinical isolates (shown in Figures 1 and 2, respectively) of P. aeruginosa and ATCC 27853 reference strain (shown in Figure 3) of P. aeruginosa indicate that compounds 2 and 3 achieved 4 - 6 log 10 kill within 2 h.
  • Example 4 Displacement of dansyl-polymyxin bound to lipopolysaccharide (LPS) from P. aeruginosa, Escherichia coli, K. pneumoniae and Salmonella enterica by the compounds of the invention, colistin and polymyxin B
  • Dansyl-polymyxin B (identified by the following structure, where * represents the location of cyclisation: octanoyl-Lys(dansyl)-Thr-Dab-Dab*-Dab-D-Phe-Leu-Dab-Dab-Thr*) was synthesized according to one or more of the representative syntheses described in Example 1 using dansyl-appended lysine. Suspensions of purified LPS (3 mg/L) from P. aeruginosa (Sigma- Aldrich, cat # L9143), E. coli (Sigma- Aldrich, cat # L2630), K. pneumoniae (Sigma- Aldrich, cat # L4268) and (S 1 .
  • enterica (Sigma- Aldrich, cat # L6511) were prepared in 5 mM HEPES buffer (pH 7.2). LPS was added into a quartz cuvette containing 1 niL of the same buffer, after which time aliquots of dansyl-polymyxin B solution were titrated at 2 min intervals until fluorescence intensity reached a plateau. Fluorescence was measured using a Cary Eclipse Fluorescence spectrophotometer (Varian, Mulgrave, Victoria Australia) set at an excitation wavelength of 340 nm. Slit widths were set to 5 and 10 nm for the excitation and emission monochromators, respectively. Emission spectra were collected from a wavelength of 400 - 650 nm (the emission maxima for bound dansyl-polymyxin B was observed at approximately 485 nm).
  • Fluorescence enhancement was determined from the integrated area under the emission spectra.
  • the K d of the LPS-dansyl-polymyxin complex was determined by non-linear regression analysis of the binding isotherms.
  • the background corrected dansyl-polymyxin binding fluorescence data were fitted to a one-site binding model (EqI):
  • ⁇ F represents the specific fluorescence enhancement upon the addition of dansyl- polymyxin B to a fixed concentration of LPS
  • ⁇ F max is the maximum specific fluorescence enhancement at saturation
  • K d represents the dissociation constant for dansyl-polymyxin B binding to LPS obtained from the concentration of dansyl-polymyxin B equivalent to half F max determined from the data fit
  • [L] represents the free concentration of dansyl- polymyxin B.
  • Dansyl-polymyxin B was added to a quartz cuvette containing LPS at a concentration necessary to obtain 90 to 100% of the maximum fluorescence when bound. Displacement of dansyl-polymyxin B by compounds 2, 3 and 5, polymyxin B and colistin, tested separately, was measured as the corresponding decrease in fluorescence upon the progressive titration of aliquots of stock solutions of the compound to be tested at 2-minute intervals, until no further decrease in fluorescence was observed. Fluorescence readings were corrected for dilution before plotting the fraction of dansyl- polymyxin B bound as a function of displacing test compound concentration.
  • the concentration of test compound required to displace 50 % of the bound dansyl-polymyxin B (I 50 ) was determined by fitting the fluorescence data to a sigmoidal dose-response model which assumed a single class of binding sites (Eq 2):
  • I 50 is the midpoint of competition and is defined as the concentration of displacer at which the maximum fluorescence intensity (F max ) of the dansyl-polymyxin B saturated complex is reduced to 50 % of the initial value
  • F m i n represents the maximum dansyl- polymyxin B displacement produced by the competitor and is defined by the bottom plateau of the displacement curve
  • [L] represents the concentration of the competitor.
  • the inhibition constant (Ki) was determined from the following equation (Eq 3):
  • Ki [I 50 ]/(l+[dansyl- ⁇ olymyxin B] ⁇ s JK. d dansyi-poiymyxin B) (Eq 3)
  • Kd dansyi-poiymyxin B represents the dissociation constant for the LPS-dansyl-polymyxin B complex. All data modeling operations were performed with GraphPad Prism V4.0 software (GraphPad software, San Diego, CA, USA).
  • Hemolysis was assessed using a modified method (Worlitzsch D, Kaygin H, Steinhuber A et al. Effects of amoxicillin, gentamicin, and moxifloxacin on the hemolytic activity of Staphylococcus aureus in vitro and in vivo. Antimicrob. Agents Chemother. (2001) 45, 196-202) with healthy human red blood cells (Australian Red Cross). Tested concentrations of compound 2, compound 3, colistin and polymyxin B were 0.5 to 128 mg/L. A 2% solution of Triton X-100 was employed as a positive control and red blood cells in isotonic phosphate buffer - saline was a negative control.
  • Example 6 In vivo efficacy of compound 3 and colistin in neutropenic mouse lung infection model
  • mice Six-week old, specific-pathogen-free, female Swiss mice (22 - 26 g) were purchased from Monash Animal Services (Clayton, Victoria, Australia). Mice were fed normal mouse chow and water ad libitum and were housed in M.I.C.E. ® cages (Australian Animal Care Systems Pty Ltd, Keilor, Victoria, Australia) at room temperature (20 - 23 0 C). The animals were maintained in accordance with the criteria of the Australian code of practice for the care and use of animals for scientific purposes.
  • mice were rendered neutropenic by intraperitoneal administration of two doses of cyclophosphamide (Endoxan ® , Baxter Healthcare Pty Ltd, NSW, Australia) 4 days (150 mg/kg) and 1 day (100 mg/kg) prior to experimental infection (Dudhani RV, Turnidge JD, Coulthard K et al Elucidation of the pharmacokinetic/pharmacodynamic determinant of colistin activity against Pseudomonas aeruginosa in murine thigh and lung infection models. ⁇ ntimicrob. Agents Chemother. (2010) 54, 1117-24). Before introducing the inoculum into lungs, mice were anesthetized very lightly with isoflurane by inhalation.
  • Lung infection was produced by introducing intranasally, via a 29-gauge needle, 50 ⁇ L of a suspension of bacterial cells ( ⁇ 10 8 CFLVmL) in early logarithmic phase.
  • the bacterial suspension was delivered in ⁇ 10 ⁇ L volumes which, when placed directly in the nares of the anesthetized mouse, was inhaled spontaneously. This procedure was repeated until animals received the entire 50 ⁇ L of bacterial suspension. Thereafter, animals were held in a vertical position with head up for 1 min.
  • Administration of colistin (a single subcutaneous dose of 40 mg/kg) or compound 3 (a single subcutaneous dose of 40 mg/kg) occurred 2 h after inoculation by which time infection was reproducibly established and bacterial load in the lung was determined as time zero.
  • lungs were collected aseptically and homogenized in 2 mL of normal saline in a polystyrene round-bottom tube (Becton Dickinson, NJ, USA). The homogenate was mixed with a further 2 mL of sterile saline and filtered through a sterile filter bag (280 ⁇ m, Bagpage ® , Interscience, France). The filtrate was serially diluted with saline and 50 ⁇ L aliquots were plated on nutrient agar plates using a WASP2 ® spiral plater (Don Whitley Scientific Ltd, England).

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Abstract

La présente invention concerne des composés antimicrobiens et leurs utilisations, et en particulier des antibiotiques peptidiques qui peuvent être utilisés dans le traitement d'infections par des bactéries Gram-négatives.
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WO2012051663A1 (fr) * 2010-10-21 2012-04-26 Monash University Composés antimicrobiens
WO2015149131A1 (fr) * 2014-04-01 2015-10-08 Monash University Dérivés de polymyxine utilisés comme composés antimicrobiens
US9234006B2 (en) 2011-11-18 2016-01-12 Novacta Biosystems Limited Compounds
WO2016100578A2 (fr) 2014-12-16 2016-06-23 Micurx Pharmaceuticals, Inc. Polymyxines antimicrobiennes pour le traitement d'infections bactériennes
WO2017209719A1 (fr) * 2016-06-01 2017-12-07 Gazel Deniz Effet antimicrobien du bleu de méthylène sur les bactéries acinetobacter baumannii résistantes à la colistine
WO2018108154A1 (fr) * 2016-12-16 2018-06-21 中国医学科学院医药生物技术研究所 Dérivé de polyximine, procédé de préparation et application associés
US10407467B2 (en) 2013-05-22 2019-09-10 New Pharma Licence Holdings Limited Polymyxin derivatives and their use in combination therapy together with different antibiotics
CN110845579A (zh) * 2019-08-08 2020-02-28 上海市食品药品检验所 一种多黏菌素e组分及其光化学产物和液相色谱-质谱分析方法
US11225505B2 (en) 2015-09-29 2022-01-18 Monash University Antimicrobial polymyxin derivative compounds
US11279733B2 (en) 2017-11-02 2022-03-22 The University Of Queensland Peptide antibiotics
US11459357B2 (en) 2018-06-25 2022-10-04 Spero Therapeutics, Inc. Polymyxin compounds
US12146004B2 (en) * 2014-11-26 2024-11-19 Spero Therapeutics, Inc. Polymyxin compounds and uses thereof
WO2024250929A1 (fr) * 2023-06-07 2024-12-12 中国医学科学院医药生物技术研究所 Groupe de composés lipopeptidiques alcalins cycliques, son procédé de préparation et son utilisation

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WO2012051663A1 (fr) * 2010-10-21 2012-04-26 Monash University Composés antimicrobiens
US9234006B2 (en) 2011-11-18 2016-01-12 Novacta Biosystems Limited Compounds
US10407467B2 (en) 2013-05-22 2019-09-10 New Pharma Licence Holdings Limited Polymyxin derivatives and their use in combination therapy together with different antibiotics
USRE48335E1 (en) 2014-04-01 2020-12-01 Monash University Polymyxin derivatives as antimicrobial compounds
CN106414480B (zh) * 2014-04-01 2020-08-04 莫纳什大学 作为抗微生物化合物的多黏菌素衍生物
CN106414480A (zh) * 2014-04-01 2017-02-15 莫纳什大学 作为抗微生物化合物的多黏菌素衍生物
WO2015149131A1 (fr) * 2014-04-01 2015-10-08 Monash University Dérivés de polymyxine utilisés comme composés antimicrobiens
AU2015240435B2 (en) * 2014-04-01 2019-09-19 Monash University Polymyxin derivatives as antimicrobial compounds
US10047126B2 (en) 2014-04-01 2018-08-14 Monash University Polymyxin derivatives as antimicrobial compounds
US12146004B2 (en) * 2014-11-26 2024-11-19 Spero Therapeutics, Inc. Polymyxin compounds and uses thereof
WO2016100578A3 (fr) * 2014-12-16 2016-08-11 Micurx Pharmaceuticals, Inc. Polymyxines antimicrobiennes pour le traitement d'infections bactériennes
CN107257803A (zh) * 2014-12-16 2017-10-17 盟科医药技术公司（开曼群岛） 用于治疗细菌感染的多粘菌素类抗菌剂
WO2016100578A2 (fr) 2014-12-16 2016-06-23 Micurx Pharmaceuticals, Inc. Polymyxines antimicrobiennes pour le traitement d'infections bactériennes
US9771394B2 (en) 2014-12-16 2017-09-26 Micurx Pharmaceuticals, Inc. Antimicrobial polymyxins for treatment of bacterial infections
KR102585108B1 (ko) * 2014-12-16 2023-10-05 상하이 미큐알엑스 파마슈티컬 컴퍼니 리미티드 세균 감염의 치료를 위한 항미생물성 폴리믹신
KR20170086671A (ko) * 2014-12-16 2017-07-26 미큐알엑스 파마슈티컬스, 인코포레이티드 세균 감염의 치료를 위한 항미생물성 폴리믹신
US11225505B2 (en) 2015-09-29 2022-01-18 Monash University Antimicrobial polymyxin derivative compounds
WO2017209719A1 (fr) * 2016-06-01 2017-12-07 Gazel Deniz Effet antimicrobien du bleu de méthylène sur les bactéries acinetobacter baumannii résistantes à la colistine
AU2017376711B2 (en) * 2016-12-16 2020-07-16 Institute Of Medicinal Biotechnology, Chinese Academy Of Medical Sciences Polymyxin derivative, preparation method and application thereof
JP2020504100A (ja) * 2016-12-16 2020-02-06 中国医学科学院医薬生物技術研究所 ポリミキシン誘導体及びその製造方法と応用
WO2018108154A1 (fr) * 2016-12-16 2018-06-21 中国医学科学院医药生物技术研究所 Dérivé de polyximine, procédé de préparation et application associés
US11279733B2 (en) 2017-11-02 2022-03-22 The University Of Queensland Peptide antibiotics
US11459357B2 (en) 2018-06-25 2022-10-04 Spero Therapeutics, Inc. Polymyxin compounds
CN110845579A (zh) * 2019-08-08 2020-02-28 上海市食品药品检验所 一种多黏菌素e组分及其光化学产物和液相色谱-质谱分析方法
CN110845579B (zh) * 2019-08-08 2022-04-19 上海市食品药品检验研究院 一种多黏菌素e组分及其光化学产物和液相色谱-质谱分析方法
WO2024250929A1 (fr) * 2023-06-07 2024-12-12 中国医学科学院医药生物技术研究所 Groupe de composés lipopeptidiques alcalins cycliques, son procédé de préparation et son utilisation

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