Evolution of Daptomycin Resistance in Coagulase-Negative Staphylococci Involves Mutations of the Essential Two-Component Regulator WalKR
Evolution of Daptomycin Resistance in Coagulase-Negative Staphylococci Involves Mutations of the Essential Two-Component Regulator WalKR
复制标题
DOI：
10.1128/aac.01926-18
复制
发表时间：
2019-03-01
影响因子：
4.9
通讯作者：
Peleg, Anton Y.
中科院分区：
文献类型：
--
作者：
Jiang, Jhih-Hang;Dexter, Carina;Peleg, Anton Y.
凝固酶阴性葡萄球菌（CoNS）是医疗保健和医疗器械相关感染的主要原因之一。新出现的抗生素耐药性使CoNS引起的全身感染的治疗变得复杂。在这里，我们描述了4年多来三级医院临床CoNS菌株的抗生素耐药性的流行情况，我们观察到对达托霉素的耐药性显著增加。值得注意的是，这些达托霉素耐药（DAP-R）CoNS中的大多数为头葡萄球菌。capitis和Staphylococcus epidermidis进行体外达托霉素暴露以产生DAP-R CoNS突变体。与金黄色葡萄球菌不同，在DAP-R CoNS菌株中未观察到细胞表面电荷的改变，但生物膜形成受到损害。DAP-R CoNS菌株的全基因组测序分析鉴定了walKR中的单核苷酸多态性（SNP），walKR是控制细胞壁生物发生的基本双组分调控系统。对17株DAP-R CoNS临床分离株的walK和walR进行PCR和测序，鉴定出7种非同义突变。结果通过在S.表皮，这导致对达托霉素和万古霉素的敏感性降低。这项研究强调了CoNS在发展达托霉素耐药性中的重要性，并表明walKR在葡萄球菌物种中共享，并参与抗生素耐药性的发展。值得注意的是，我们没有观察到负责磷脂生物合成的基因突变或细胞表面电荷改变，这表明CoNS中达托霉素敏感性降低可能以不同于S的方式出现。金黄色。
Coagulase-negative staphylococci (CoNS) represent one of the major causes of health care- and medical device-associated infections. Emerging antimicrobial resistance has complicated the treatment of systemic infections caused by CoNS. Here, we describe the prevalence of antimicrobial resistance in clinical CoNS strains from a tertiary care hospital over a 4-year period, and we observed a significant increase in resistance to daptomycin. Notably, Staphylococcus capitis accounted for the majority of these daptomycin-resistant (DAP-R) CoNS. To further investigate the mechanisms of daptomycin resistance in CoNS, daptomycin-susceptible clinical strains of S. capitis and Staphylococcus epidermidis underwent in vitro daptomycin exposure to generate DAP-R CoNS mutants. Unlike that seen with Staphylococcus aureus, alteration of cell surface charge was not observed in the DAP-R CoNS strains, but biofilm formation was compromised. Whole-genome sequencing analysis of the DAP-R CoNS strains identified single nucleotide polymorphisms (SNPs) in walKR, the essential two-component regulatory system controlling cell wall biogenesis. PCR and sequencing of walK and walR from 17 DAP-R CoNS clinical isolates identified seven nonsynonymous mutations. The results were confirmed by the recreation of the walK SNP in S. epidermidis, which resulted in reduced susceptibility to daptomycin and vancomycin. This study highlights the significance of CoNS in evolving daptomycin resistance and showed that walKR is shared among the staphylococcal species and is involved in antibiotic resistance development. Notably, we did not observe mutations in genes responsible for phospholipid biosynthesis or an altered cell surface charge, suggesting that reduced daptomycin susceptibility in CoNS may emerge in a fashion distinct from that in S. aureus.