title: Beyond conventional antibiotics for the future treatment of methicillin-resistant Staphylococcus aureus infections: two novel alternatives.
abstract: The majority of antibiotics currently used to treat methicillin-resistant Staphylococus aureus (MRSA) infections target bacterial cell wall synthesis or protein synthesis. Only daptomycin has a novel mode of action. Reliance on limited targets for MRSA chemotherapy, has contributed to antimicrobial resistance. Two alternative approaches to the treatment of S. aureus infection, particularly those caused by MRSA, that have alternative mechanisms of action and that address the challenge of antimicrobial resistance are cationic host defence peptides and agents that target S. aureus virulence. Cationic host defence peptides have multiple mechanisms of action and are less likely than conventional agents to select resistant mutants. They are amenable to modifications that improve their stability, effectiveness and selectivity. Some cationic defence peptides such as bactenecin, mucroporin and imcroporin have potent in vitro bactericidal activity against MRSA. Antipathogenic agents also have potential to limit the pathogenesis of S aureus. These are generally small molecules that inhibit virulence targets in S. aureus without killing the bacterium and therefore have limited capacity to promote resistance development. Potential antipathogenic targets include the sortase enzyme system, the accessory gene regulator (agr) and the carotenoid biosynthetic pathway. Inhibitors of these targets have been identified and these may have potential for further development.
authors.affiliation: Department of Clinical Microbiology, Education and Research Centre, Royal College of Surgeons in Ireland, Beaumont Hospital, Dublin, Ireland. dfitzgeraldhughes@rcsi.ie
authors.forename: Deirdre
authors.initials: D
authors.lastname: Fitzgerald-Hughes
authors.forename: Marc
authors.initials: M
authors.lastname: Devocelle
authors.forename: Hilary
authors.initials: H
authors.lastname: Humphreys
mesh_terms: D000595:Amino Acid Sequence; D000900:Anti-Bacterial Agents / Q000627:therapeutic use*; D023181:Antimicrobial Cationic Peptides / Q000627:therapeutic use; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors; D006801:Humans; D053858:Metabolic Networks and Pathways / Q000187:drug effects*; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects / Q000254:growth & development / Q000472:pathogenicity*; D008969:Molecular Sequence Data; D058990:Molecular Targeted Therapy; D010456:Peptides, Cyclic / Q000627:therapeutic use; D018272:Porins / Q000627:therapeutic use; D013203:Staphylococcal Infections / Q000188:drug therapy* / Q000382:microbiology; D015534:Trans-Activators / Q000037:antagonists & inhibitors; D014774:Virulence; D024341:Xanthophylls / Q000037:antagonists & inhibitors
chemical_list: C095698:Agr protein, Staphylococcus aureus; D000900:Anti-Bacterial Agents; D023181:Antimicrobial Cationic Peptides; D001426:Bacterial Proteins; D010456:Peptides, Cyclic; D018272:Porins; D015534:Trans-Activators; D024341:Xanthophylls; C056454:bactenecin; C031841:staphyloxanthin