Abstract：
Enterococcal infections frequently show high levels of antibiotic resistance, including to cell envelope-acting antibiotics like daptomycin (DAP). While we have a good understanding of the resistance mechanisms, less is known about the control of such resistance genes in enterococci. Previous work unveiled a bacitracin resistance network, comprised of the sensory ABC transporter SapAB, the two-component system (TCS) SapRS and the resistance ABC transporter RapAB. Interestingly, components of this system have recently been implicated in DAP resistance, a role usually regulated by the TCS LiaFSR. To better understand the regulation of DAP resistance and how this relates to mutations observed in DAP-resistant clinical isolates of enterococci, we here explored the interplay between these two regulatory pathways. Our results show that SapR regulates an additional resistance operon, dltXABCD, a known DAP resistance determinant, and show that LiaFSR regulates the expression of sapRS. This regulatory structure places SapRS-target genes under dual control, where expression is directly controlled by SapRS, which itself is up-regulated through LiaFSR. The network structure described here shows how Enterococcus faecalis coordinates its response to cell envelope attack and can explain why clinical DAP resistance often emerges via mutations in regulatory components.
摘要：
肠球菌感染经常表现出高水平的抗生素耐药性，包括细胞包膜作用抗生素，如达托霉素（DAP）。虽然我们对抗性机制有很好的了解，人们对肠球菌中这种抗性基因的控制知之甚少。先前的工作揭示了杆菌肽抵抗网络，由感官ABC转运蛋白SapAB组成，双组分系统（TCS）SapRS和抗性ABC转运蛋白RapAB。有趣的是,该系统的组件最近与DAP抵抗有关，通常由TCSLiaFSR调节的角色。为了更好地了解DAP抗性的调节以及这与在DAP抗性肠球菌临床分离株中观察到的突变的关系，我们在这里探讨了这两种调节途径之间的相互作用。我们的结果表明，SapR调节额外的抗性操纵子，dltXABCD,已知的DAP抵抗决定因素，并表明LiaFSR调节sapRS的表达。这种调控结构将SapRS靶基因置于双重控制之下，其中表达直接由SapRS控制，它本身是通过LiaFSR上调的。此处描述的网络结构显示粪肠球菌如何协调其对细胞包膜攻击的反应，并可以解释为什么临床DAP抗性通常通过调节成分的突变而出现。
