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.

中文翻译：

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达托霉素和杆菌肽响应途径之间的调节相互作用协调粪肠球菌的细胞包膜抗生素耐药性响应


肠球菌感染经常表现出高水平的抗生素耐药性，包括对细胞包膜作用的抗生素，如达托霉素 (DAP)。虽然我们对耐药机制有很好的了解，但对肠球菌中此类耐药基因的控制知之甚少。先前的工作揭示了杆菌肽耐药网络，由感觉 ABC 转运蛋白 SapAB、双组分系统 (TCS) SapRS 和耐药 ABC 转运蛋白 RapAB 组成。有趣的是，该系统的组件最近与 DAP 耐药性有关，该作用通常由 TCS LiaFSR 调节。为了更好地了解 DAP 耐药性的调节以及这与 DAP 耐药性肠球菌临床分离株中观察到的突变之间的关系，我们在此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 调节一个额外的抗性操纵子dltXABCD ，这是一种已知的 DAP 抗性决定子，并表明 LiaFSR 调节sapRS的表达。这种调节结构将 SapRS 靶基因置于双重控制之下，其中表达由 SapRS 直接控制，而 SapRS 本身通过 LiaFSR 上调。这里描述的网络结构显示了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 耐药性经常通过调节成分的突变出现。