MRC Centre for Molecular Bacteriology and Infection, Imperial College London, Armstrong Road, London SW7 2AZ, UK.
Nat Microbiol. 2016 Oct 24;2:16194. doi: 10.1038/nmicrobiol.2016.194.
Daptomycin is a bactericidal antibiotic of last resort for serious infections caused by methicillin-resistant Staphylococcus aureus (MRSA). Although resistance is rare, treatment failure can occur in more than 20% of cases and so there is a pressing need to identify and mitigate factors that contribute to poor therapeutic outcomes. Here, we show that loss of the Agr quorum-sensing system, which frequently occurs in clinical isolates, enhances S. aureus survival during daptomycin treatment. Wild-type S. aureus was killed rapidly by daptomycin, but Agr-defective mutants survived antibiotic exposure by releasing membrane phospholipids, which bound and inactivated the antibiotic. Although wild-type bacteria also released phospholipid in response to daptomycin, Agr-triggered secretion of small cytolytic toxins, known as phenol soluble modulins, prevented antibiotic inactivation. Phospholipid shedding by S. aureus occurred via an active process and was inhibited by the β-lactam antibiotic oxacillin, which slowed inactivation of daptomycin and enhanced bacterial killing. In conclusion, S. aureus possesses a transient defence mechanism that protects against daptomycin, which can be compromised by Agr-triggered toxin production or an existing therapeutic antibiotic.
达托霉素是一种杀菌抗生素，是治疗耐甲氧西林金黄色葡萄球菌（MRSA）引起的严重感染的最后手段。尽管耐药性很少见，但超过 20%的病例会出现治疗失败，因此迫切需要确定并减轻导致治疗效果不佳的因素。在这里，我们表明 Agr 群体感应系统的缺失，这种情况经常发生在临床分离株中，会增强金黄色葡萄球菌在达托霉素治疗期间的存活能力。野生型金黄色葡萄球菌很快被达托霉素杀死，但 Agr 缺陷突变体通过释放结合并使抗生素失活的膜磷脂在抗生素暴露下存活下来。尽管野生型细菌也会对达托霉素产生反应释放磷脂，但 Agr 触发的小细胞溶解毒素（称为酚可溶性调节素）的分泌防止了抗生素失活。金黄色葡萄球菌的磷脂脱落是通过一个主动过程发生的，被β-内酰胺抗生素苯唑西林抑制，这减缓了达托霉素的失活并增强了细菌的杀伤作用。总之，金黄色葡萄球菌具有一种暂时的防御机制，可以抵御达托霉素，而 Agr 触发的毒素产生或现有的治疗性抗生素可以破坏这种防御机制。
