title: Pharmacology of polymyxins: new insights into an 'old' class of antibiotics.
abstract: Increasing antibiotic resistance in Gram-negative bacteria, particularly in Pseudomonas aeruginosa, Acinetobacter baumannii and Klebsiella pneumoniae, presents a global medical challenge. No new antibiotics will be available for these 'superbugs' in the near future due to the dry antibiotic discovery pipeline. Colistin and polymyxin B are increasingly used as the last-line therapeutic options for treatment of infections caused by multidrug-resistant Gram-negative bacteria. This article surveys the significant progress over the last decade in understanding polymyxin chemistry, mechanisms of antibacterial activity and resistance, structure-activity relationships and pharmacokinetics/pharmacodynamics. In the 'Bad Bugs, No Drugs' era, we must pursue structure-activity relationship-based approaches to develop novel polymyxin-like lipopeptides targeting polymyxin-resistant Gram-negative 'superbugs'. Before new antibiotics become available, we must optimize the clinical use of polymyxins through the application of pharmacokinetic/pharmacodynamic principles, thereby minimizing the development of resistance.
authors.affiliation: Drug Delivery, Disposition & Dynamics, Monash Institute of Pharmaceutical Sciences, 381 Royal Parade Parkville 3052, Victoria, Australia.
authors.forename: Tony
authors.initials: T
authors.lastname: Velkov
authors.forename: Kade D
authors.initials: KD
authors.lastname: Roberts
authors.forename: Roger L
authors.initials: RL
authors.lastname: Nation
authors.forename: Philip E
authors.initials: PE
authors.lastname: Thompson
authors.forename: Jian
authors.initials: J
authors.lastname: Li
mesh_terms: D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology* / Q000627:therapeutic use; D024901:Drug Resistance, Multiple, Bacterial; D006090:Gram-Negative Bacteria / Q000187:drug effects; D016905:Gram-Negative Bacterial Infections / Q000188:drug therapy; D006801:Humans; D008954:Models, Biological; D008958:Models, Molecular; D011113:Polymyxins / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology* / Q000627:therapeutic use; D013329:Structure-Activity Relationship
chemical_list: D000900:Anti-Bacterial Agents; D011113:Polymyxins