Drug Delivery, Disposition & Dynamics, Monash Institute of Pharmaceutical Sciences, 381 Royal Parade Parkville 3052, Victoria, Australia.
Future Microbiol. 2013 Jun;8(6):711-24. doi: 10.2217/fmb.13.39.
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.
革兰氏阴性菌（尤其是铜绿假单胞菌、鲍曼不动杆菌和肺炎克雷伯菌）的抗生素耐药性不断增加，这是一个全球性的医学挑战。由于抗生素研发渠道枯竭，在可预见的未来，这些“超级细菌”不会有新的抗生素问世。粘菌素和多黏菌素 B 由于被越来越多地用作治疗多重耐药革兰氏阴性菌感染的最后一线治疗选择。本文综述了过去十年中在理解多黏菌素化学、抗菌活性和耐药机制、结构-活性关系以及药代动力学/药效学方面取得的重大进展。在“恶菌猖獗，无药可用”的时代，我们必须采用基于结构-活性关系的方法来开发针对多黏菌素耐药革兰氏阴性“超级细菌”的新型多黏菌素类似脂肽。在新抗生素问世之前，我们必须通过应用药代动力学/药效学原则来优化多黏菌素的临床应用，从而最大程度地减少耐药性的产生。
