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WO1999026968A1 - Oligopeptides et leur utilisation comme agents antibacteriens contre des souches de staphylococcus - Google Patents

Oligopeptides et leur utilisation comme agents antibacteriens contre des souches de staphylococcus Download PDF

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Publication number
WO1999026968A1
WO1999026968A1 PCT/GB1998/003497 GB9803497W WO9926968A1 WO 1999026968 A1 WO1999026968 A1 WO 1999026968A1 GB 9803497 W GB9803497 W GB 9803497W WO 9926968 A1 WO9926968 A1 WO 9926968A1
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WIPO (PCT)
Prior art keywords
compounds
peptide
integer
leu
phe
Prior art date
Application number
PCT/GB1998/003497
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English (en)
Inventor
Barrie Walsham Bycroft
Paul Williams
Gordon Sydney Anderson Birnie Stewart
Weng Choon Chan
Philip William Mcdowell
Zina Mariam Affas
Original Assignee
The University Of Nottingham
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by The University Of Nottingham filed Critical The University Of Nottingham
Priority to AU12490/99A priority Critical patent/AU1249099A/en
Publication of WO1999026968A1 publication Critical patent/WO1999026968A1/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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/195—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from bacteria
    • C07K14/305—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from bacteria from Micrococcaceae (F)
    • C07K14/31—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from bacteria from Micrococcaceae (F) from Staphylococcus (G)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • This invention relates to a group of compounds which may be used as antibacterial agents.
  • Bacterial infections may be a primary cause of disease or they may arise following invasive treatment such as surgery or the insertion of catheters or prostheses. Since the discovery of penicillin, antibiotic drugs have been used to combat bacterial infections. However, strains of bacteria resistant to most, if not all, of the known antibiotic drugs are now emerging and new approaches for the treatment of bacterial infections are therefore of great interest.
  • Staphylococci bacteria are responsible for a number of illnesses such as food poisoning, the symptoms of which (profuse vomiting and diarrhoea) can result in rapid dehydration and occasionally prove fatal to the young and elderly. Toxins produced by certain strains of these bacteria (e.g. Staphylococcus aureus) are also the main cause of tampon-associated toxic shock syndrome. In addition, although staphylococci are not implicated as the disease agent in influenza, this illness can predispose to Staphylococcus aureus, which, as a cause of pneumonia, has one of the highest mortality rates.
  • the synthesis of virulence factors and other extracellular proteins by Staphylococcus aureus is globally controlled by the agr locus.
  • the agr locus consists of two divergent transcription units driven by promoters P2 and P3.
  • the P3 transcript RNA III rather than any protein, is the effector of the agr response which involves the up-regulation of genes encoding secreted proteins (e.g., exotoxins) and down-regulation of genes encoding surface proteins (or cell wall proteins) .
  • the thioester material which was synthesised failed to activate their reporter assay.
  • the synthetic peptides are effectors of the agr response and are thus agonists for the later stages of virulence, such as the expression of exotoxin and antagonists for the earlier stages of virulence such as the expression of cell proteins.
  • the same peptides may be inhibitors of the agr response and therefore antagonists, by this definition, for other strains of bacteria.
  • A, B, E and D are independently selected from residues of natural or synthetic amino acids or substituted derivatives thereof;
  • n is zero or an integer from 1 to 5;
  • X is S, O or NR 3 ;
  • R 1 , R 2 and R 3 are independently selected from hydrogen, C j to C 6 alkyl, C j to C 6 acyl and C, to C 6 alkoxycarbonyl or, when m is zero, R 1 and R 2 may be linked so as to form a heterocyclic ring with the N atom to which R 2 is attached; and
  • Z or independently each Z when m is an integer from 2 to 5, is a residue of a natural or synthetic amino acid or a substituted derivative thereof,
  • the compounds of the invention may have either agonist or antagonist activity (i.e., up- or down-regulation of the agr response, respectively) with respect to the production of exotoxins by bacteria.
  • those compounds which are agonists by this definition antagonise the earlier stages in virulence such as the production of cell wall proteins by the bacteria.
  • the compounds having antagonist activity are agonists for the production of cell wall proteins.
  • agonists and antagonists are both potentially useful in the treatment and/or prevention of bacterial infection.
  • the agonists, by down-regulating the earlier stages of virulence may be useful for prophylaxis whereas the antagonists will be of use in the treatment of infections at a later stage. Essentially, the compounds interfere with the normal operation of the bacterial cells.
  • the compounds of the invention in which m is not equal to zero are likely to have agonist activity where they resemble the naturally occurring peptides but they may be antagonists for other strains.
  • m is equal to zero. It has surprisingly been found that compounds of this type act as antagonists in a number of different bacterial strains. Hence, this sub-class of the compounds of the invention constitutes a route to preventing or treating bacterial infections, over a range of different strains, by down regulating the production of harmful exotoxins and other factors associated with the later stages of virulence.
  • A, B, E and D are independently selected from residues of natural or synthetic amino acids or substituted derivatives thereof.
  • Each Z in the (Z) m chain is similarly independently selected from residues of these types of amino acid. Any of the twenty natural amino acids are suitable for A, B, E, D and Z.
  • the natural amino acids are as follows:
  • Residues of amino acids which are not naturally occurring are also suitable for A, B, E and D, although these are currently less preferred.
  • the residues may be substituted derivatives of the naturally occurring or synthetic amino acids.
  • the amino acid residue comprises an alkyl, aryl or heteroaryl group
  • this may be substituted with one or more groups such as C j -Ce alkyl, hydroxy or halo (i.e. , F, CI, Br or I).
  • the residues of the amino acids contain functional groups such as thiol (-SH), carboxylic acid (-COOH) or amino (-NH 2 ), these may be converted to other species.
  • the thiol groups may be alkylated with a C r C 6 alkyl group
  • the carboxylic acid may be a salt, an ester or an amide
  • the amino group may be an addition salt or may be N-alkylated or N-acylated with C C 6 alkyl or C C 6 acyl groups, respectively.
  • Each amino acid residue may be of substantially one enantiomer, an optically active mixture of enantiomers or a racemic mixture. At least one of the amino acids of A, B, E, D and Z or each Z is preferably an L-isomer and, more preferably, they are all L- isomers.
  • Suitable values for A, B, E and D, for example, are respectively:
  • X is S and the compounds of the invention are thiolactones.
  • R 1 is preferably C C 6 acyl, such as acetyl, and R 2 is preferably H.
  • alkyl covers branched and unbranched alkyl groups, optionally substituted by one or more halogen atoms (e.g., fluorine or chlorine).
  • halogen atoms e.g., fluorine or chlorine.
  • acyl and “alkoxycarbonyl” are defined in a corresponding manner.
  • the asymmetric carbon atom bound to the (CH 2 ) group in the compounds of the invention may be of L- or D- stereochemistry or a mixture of these isomers (such as a racemate) .
  • the same considerations with regard to optical activity apply to the overall compound.
  • the compounds of the invention may be in the form of pharmaceutically acceptable acid or base addition salts or prodrugs.
  • Suitable prodrugs include in vivo hydrolysable esters or amides of the compounds, where they contain a hydroxy group or an amino group, respectively.
  • the compounds of the invention may be anhydrous or they may be solvates (e.g., hydrates).
  • the invention also provides a compound of formula (II):
  • a ' , B ' , E ' and D ' are Asp, Phe, lie and Met, respectively, and Y is H-Tyr-Ser-Thr-; or (ii) A ' , B ' , E and D ' are Asn, Ala, Tyr and Phe, respectively, and Y is H-Asp-lle; or (iii) A ' , B ' , E and D ' are Asp, Phe, Leu and Leu, respectively, and Y is H-Tyr-lle-Asn; or (iv) A ' , B ' , E ' and D ' are Ser, Ser, Leu and Phe, respectively, and Y is H-Gly-Val-Asn-Ala- in substantially pure form. These are the naturally occurring peptides which have not previously been successfully synthesised and obtained in substantially pure form.
  • the invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the invention and a pharmaceutically acceptable diluent or carrier.
  • a pharmaceutically acceptable diluent or carrier for example, creams or ointments may be prepared for topical application, sterile injectable compositions may be formulated or the compositions may be made suitable for oral administration e.g., by being in the form of tablets, suspensions or solutions.
  • the invention also relates to the use of the compounds of the invention in the manufacture of a medicament for the treatment and/or prevention of bacterial infections.
  • the invention relates to a method for the treatment and/or prevention of bacterial infections in humans or animals which comprises administering a therapeutically effective amount of a compound of the invention to a patient in need thereof.
  • the compounds of the invention have been found to be particularly effective in down-regulating virulence in Gram-positive bacteria such as Staphylococci.
  • the Staphylococci may be from a number of different strains such as Staphylococcus aureus or the coagulase-negative strains such as Staphylococcus epidermidis.
  • the compounds of the invention preferably antagonise the production of exotoxin(s) by the bacteria.
  • the article may be a tampon and the use of the compound in this context may prevent, or reduce the likelihood of, toxic shock syndrome.
  • Toxic shock syndrome is believed to be caused by the bacterial exotoxin TSST-1 .
  • the article of the invention may be a surgical prosthesis or a wound dressing.
  • the surgical prosthesis may be intended for long-term insertion into the body (e.g., a cardiac pacemaker) or for short-term insertion (e.g., a catheter).
  • the invention also provides a process for producing a compound of the invention which comprises the following steps:
  • Step (a) may involve conventional solid phase peptide synthesis (e.g., Fmoc/tBu) with the functional groups in the amino acids or amino acid residues protected with standard protecting groups, where necessary.
  • Step (b) may be carried out using carbodiimide-based coupling conditions which are, again, conventional.
  • the assembled resin-bound protected peptide (2) (0.1 mmol) was first swollen in DCM (HPLC grade, 1 0 ml) by stirring at room temperature for 20 min. To the stirred suspension was added a solution of 1 .0% TFA in DCM ( 1 0 ml) . The suspension was stirred for 1 -2 min during which the resin acquired a deep red colouration. The colourless solution of protected peptide was then filtered into a mixture of pyridine (0.3 ml, 3.71 mmol) in methanol ( 1 5 ml) and the resin was washed with 50% DCM in methanol (2 x 1 5 ml).
  • Compound 4 was purified by RP-HPLC using a Kromasil ® C 8 ( 1 0 x 1 50 mm) column on a Waters ® 51 0 HPLC system and the eluant was monitored by UV absorbance at 220 mm using a Waters ® 484 tunable absorbance detector.
  • the eluents were solvent A; 0.06% TFA in water and solvent B; 0.06% TFA in 90% acetonitrile/water.
  • Mass spectra were recorded by LC-MS liquid chromatography or electrospray on Fisons ® VG MicroMass Platform.
  • Staphylococcus aureus RN6390B was grown in CYGP broth at 37°C with shaking to stationary phase (overnight culture) . Cells were removed by centrifugation at 4°C. The supernatant was filtered (0.22 ⁇ m filter, Gelman ®). The filtrate was stored at -80°C and used as a source of activator e.g., for positive controls and in the experiments to test for inhibition.
  • the ⁇ -lactamase reporter used in this study contains the promoter region of the RNAIII transcript (P3) linked to a staphylococcal ⁇ -lactamase gene (blaZ) (P3-blaZ), within the cloning vector pSA3800 (Ross 1 989, Novick et al., 1 995).
  • the activator assay was carried out as follows: the Staphylococcus aureus strain RN6390B (agr + ) with the P3-blaZ fusion plasmid pRN6683 was grown in CYGP broth (Appendix A) (starting at 7.5 X 1 0 7 cells per ml) at 37 °C with shaking to 4.5 X 1 0 8 cells per ml. To 45 ⁇ l of cells, 5 ⁇ l of synthetic peptide ( 1 .92 ⁇ g/ml) or activator or CYGP (negative control) was added.
  • ⁇ - lactamase activity was measured by the nitrocefin method (O'Callaghan et al., 1 972) modified as follows. Culture samples were diluted with CYGP broth plus 5 mM sodium azide to a final volume of 50 ⁇ l and transferred to a microtiter plate (96 well) . Nitrocefin solution (50 ⁇ l of 1 25 ⁇ g/ml in recommended dilution buffer, Oxoid, Basingstoke, England) was added and the plate was incubated with shaking at 37 °C. The plate reader was set to read the absorbance at 492 and 690 nm.
  • the assays for the inhibition of P3 were carried out as for the activation assays with the following modification. 5 ⁇ l of the activator preparation along with 5 ⁇ l of the substance to be tested for inhibition were added to 45 ⁇ l of exponential phase cells. Ali controls were carried out in total volume of 55 ⁇ l. See table 1 for results.
  • RN6390B suspended in PBS (see appendix A) was used as a starting innoculum. This was prepared as follows: a large colony of RN6390B grown on LB agar was suspended in 500 ⁇ l of sterile PBS. Each of the peptides was added at a concentration of 1 .92 ⁇ g/ml and the cultures grown at 37°C with shaking.
  • the cells were grown and peptide added as for the ⁇ - haemolysin experiments except for the following A 1 ml sample was taken during exponential phase and an equivalent number of cells at stationary phase (see table 3 for details), and the cells harvested by centrifugation.
  • the bacterial pellets were then incubated with 25 ⁇ l of lysostaphin ( 1 00 ⁇ g/ml, Sigma) and 25 ⁇ l of lysozyme ( 25 mg/ml) for 1 hour at 37°C.
  • the samples were boiled for 5 minutes in 2X loading buffer (see appendix A) and subsequently spun for 2 minutes in a microcentrifuge.
  • the samples were then loaded onto a 1 2% SDS PAGE gel (Laemmli, 1 970) and electrophoresed at 1 50 volts until the dye front reached the bottom of the gel.
  • the proteins were then Western blotted onto a nitro-cellulose membrane (Biotrace NT, Gelman Sciences,) at 1 00 volts for 90 minutes (Towbin et al, 1 979) .
  • the membrane was subsequently blocked using 3% Bovine serum albumin (BSA) (Sigma) in PBS and then probed with horseradish peroxidase-conjugated rabbit anti-rat IgG immunoglobulins (Dakopatts) ( 1 /1 000 in PBS) for 2 hours and developed using 4-chloro-1 -napthol (Sigma) as a substrate.
  • BSA Bovine serum albumin
  • Dakopatts horseradish peroxidase-conjugated rabbit anti-rat IgG immunoglobulins
  • the blot was then scanned using Phoretix image analysis and the intensity of each band quantified, see table 3.
  • S.aureus strain KH 1 1 87A was grown and peptide added as for the ⁇ -haemolysin experiments except that brain heart infusion broth was used instead of CYGP broth. All samples were grown until they reached an OD 540 of 2.0. The cells were removed by centrifugation and the supernatant was filter sterilized (0.22 ⁇ m Millipore filter). The sample was then centrifuged through a Microcon 1 0 filter (Amicon; 1 0 kDa cut-off) and the resulting retentate made up to 50 ⁇ l with PBS.
  • Samples plus a purified preparation of TSST-1 as a control were subjected to SDS-PAGE (1 2% separating gel) and either stained with Coomassie brilliant blue or Western blotted onto a nitrocellulose membrane and processed as described in section (c) for protein A.
  • PBS Phosphate buffered saline (0.07 M phosphate, 1 50 mM
  • PBSA PBS containing 1 mg/ml bovine serum albumin (BSA,
  • the agr P2 operon an autocatalytic sensory transduction system in Staphylococcus aureus. Mol. Gen. Genet. 248: 446-458.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Genetics & Genomics (AREA)
  • Biophysics (AREA)
  • General Health & Medical Sciences (AREA)
  • Biochemistry (AREA)
  • Medicinal Chemistry (AREA)
  • Molecular Biology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Peptides Or Proteins (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

L'invention concerne des composés représentés par la formule (I). Dans cette formule, A, B, E et D sont sélectionnés indépendamment à partir de restes d'acides aminés synthétiques ou naturels ou de dérivés de ceux-ci; m est égal à zéro ou à un nombre entier compris entre 1 et 5; n est un nombre entier compris entre 1 et 5; X représente S, O ou NR?3; R1, R2 et R3¿ sont sélectionnés indépendamment à partir du groupe constitué par hydrogène, C¿1?-C6 alkyle, C1-C6 acyle et C1-C6 alcoxycarbonyle ou, lorsque m est égal à zéro, R?1 et R2¿ peuvent être liés de manière à former un anneau hétérocyclique avec l'atome N auquel R2 est rattaché; et Z ou chaque Z indépendamment, lorsque m est un nombre entier compris entre 2 et 5, est un reste d'acide aminé naturel ou synthétique ou un dérivé substitué de celui-ci, les liaisons de peptide de la molécule étant éventuellement substituées sur l'atome d'azote par C¿1?-C6 alkyle. L'invention concerne également des sels acides, des sels d'addition de base, ou des promédicaments pharmaceutiquement acceptables des composés susmentionnés, constituant des antagonistes de la production d'exotoxine ou de la synthèse protéique des parois cellulaires due à une bactérie telle que Staphylococcus aureus, ce qui leur permet d'être utilisés en tant qu'agents antibactériens.
PCT/GB1998/003497 1997-11-26 1998-11-24 Oligopeptides et leur utilisation comme agents antibacteriens contre des souches de staphylococcus WO1999026968A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU12490/99A AU1249099A (en) 1997-11-26 1998-11-24 Oligopeptides and their use as antibacterial agents against staphylococcus strains

Applications Claiming Priority (2)

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GB9724859.5 1997-11-26
GBGB9724859.5A GB9724859D0 (en) 1997-11-26 1997-11-26 Compounds and their use as antibacterial agents

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Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999067286A3 (fr) * 1998-06-24 2000-03-16 Univ Rockefeller Nouveaux peptides de staphylocoques utilises pour des interferences bacteriennes
US6337385B1 (en) 1998-06-24 2002-01-08 The Rockefeller University Staphylococcus peptides for bacterial interference
WO2008022800A1 (fr) * 2006-08-24 2008-02-28 Leibniz-Institut Für Pflanzenbiochemie Procédé de fabrication de produits de condensation de dérivés de glycine n-substituée (peptoïdes) par des réactions séquentielles de ugi à plusieurs composants
US8729013B2 (en) 2004-08-26 2014-05-20 The University Of Western Ontario Methods of inhibiting staphylobactin-mediated iron uptake in S. aureus
US9227996B2 (en) 2013-03-11 2016-01-05 Wisconsin Alumni Research Foundation Peptide-based quorum sensing inhibitors for the attenuation of virulence in Staphylococcus aureus
WO2018109042A3 (fr) * 2016-12-13 2018-07-26 Ferring B.V. Peptides antimicrobiens
US20190038735A1 (en) * 2016-02-02 2019-02-07 Stc.Unm Vlp-based vaccines for targeting staphylococcus aureus secreted virulence factors
US10597372B2 (en) 2016-12-21 2020-03-24 Wisconsin Alumni Research Foundation Simplified structural mimetics of AIPS as quorum sensing inhibitors

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996010579A1 (fr) * 1994-10-04 1996-04-11 New York University Blocage de l'expression des facteurs de virulence du staphylocoque dore
WO1997044349A1 (fr) * 1996-05-22 1997-11-27 New York University BLOCAGE DE L'EXPRESSION DE L'AGGRESSINE DANS $i(S. AUREUS)

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996010579A1 (fr) * 1994-10-04 1996-04-11 New York University Blocage de l'expression des facteurs de virulence du staphylocoque dore
WO1997044349A1 (fr) * 1996-05-22 1997-11-27 New York University BLOCAGE DE L'EXPRESSION DE L'AGGRESSINE DANS $i(S. AUREUS)

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
JI E.A.: "BACTERIAL INTERFERENCE CAUSED BY AUTOINDUCING PEPTIDE VARIANTS", SCIENCE, vol. 276, 27 June 1997 (1997-06-27), LANCASTER, PA US, pages 2027 - 2030, XP002095450 *
JI E.A.: "CELL DENSITY CONTROL OF STAPHYLOCOCCAL VIRULENCE MEDIATED BY AN OCTAPEPTIDE PHEROMONE", PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF USA, vol. 92, December 1995 (1995-12-01), WASHINGTON US, pages 12055 - 12059, XP002095451 *

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999067286A3 (fr) * 1998-06-24 2000-03-16 Univ Rockefeller Nouveaux peptides de staphylocoques utilises pour des interferences bacteriennes
US6337385B1 (en) 1998-06-24 2002-01-08 The Rockefeller University Staphylococcus peptides for bacterial interference
US6953833B2 (en) 1998-06-24 2005-10-11 The Rockefeller University Staphylococcus peptides for bacterial interference
US8729013B2 (en) 2004-08-26 2014-05-20 The University Of Western Ontario Methods of inhibiting staphylobactin-mediated iron uptake in S. aureus
WO2008022800A1 (fr) * 2006-08-24 2008-02-28 Leibniz-Institut Für Pflanzenbiochemie Procédé de fabrication de produits de condensation de dérivés de glycine n-substituée (peptoïdes) par des réactions séquentielles de ugi à plusieurs composants
US9227996B2 (en) 2013-03-11 2016-01-05 Wisconsin Alumni Research Foundation Peptide-based quorum sensing inhibitors for the attenuation of virulence in Staphylococcus aureus
US20190038735A1 (en) * 2016-02-02 2019-02-07 Stc.Unm Vlp-based vaccines for targeting staphylococcus aureus secreted virulence factors
US10821167B2 (en) * 2016-02-02 2020-11-03 Unm Rainforest Innovations VLP-based vaccines for targeting Staphylococcus aureus secreted virulence factors
WO2018109042A3 (fr) * 2016-12-13 2018-07-26 Ferring B.V. Peptides antimicrobiens
US10597372B2 (en) 2016-12-21 2020-03-24 Wisconsin Alumni Research Foundation Simplified structural mimetics of AIPS as quorum sensing inhibitors
US11560361B2 (en) 2016-12-21 2023-01-24 Wisconsin Alumni Research Foundation Simplified structural mimetics of AIPS as quorum sensing inhibitors
US12139464B2 (en) 2016-12-21 2024-11-12 Wisconsin Alumni Research Foundation Simplified structural mimetics of AIPS as quorum sensing inhibitors

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GB9724859D0 (en) 1998-01-21

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