目的：金黄色葡萄球菌中达托霉素（DAP）的耐药性并不常见，但有关DAP治疗期间出现耐药性的报道越来越多。大多数临床DAP抗性金黄色葡萄球菌分离株研究了mprF基因中携带的突变。本研究的目的是确定临床对甲氧西林敏感的金黄色葡萄球菌（MSSA）分离株（DAP易感和DAP耐药）之间的突变。另外，评估了先前与DAP抗性相关的基因的活性。材料和方法：通过全基因组测序（WGS）和逆转录 - 定量实时PCR（RT-qPCR）分析来自患有左侧心内膜炎的患者的两种MSSA分离物。在开始治疗之前获得第一种易受DAP影响的分离物，并且在DAP治疗4周后回收第二种分离物DAP抗性。结果：DAP易感基因和其DAP抗性变体的完整基因组的比较鉴定了两个非同义和一个同义突变。非同义突变由mprF中的S829L取代和vraS中的T331I取代组成。 RT-qPCR实验揭示了DAP抗性变体中vraS，dltA，mprF和sceD基因的表达增加。引人注目的是，DAP显着下调了dltA和mprF基因的表达。结论：mprF和vraS基因之前与DAP抗性相关，然而，此研究中描述的突变中没有一个先前被鉴定并且与DAP抗性相关。此外，我们提供了对金黄色葡萄球菌的DAP作用的新见解，其中抗生素降低了DAP抗性中关键基因的表达。

Objectives: Daptomycin (DAP) resistance in Staphylococcus aureus is uncommon but there are increasing reports of the emergence of resistance during DAP therapy. Most clinical DAP-resistant S. aureus isolates investigated carried mutations in the mprF gene. The aim of this study was to identify mutations between a clinical pair of methicillin-susceptible S. aureus (MSSA) isolates (DAP-susceptible and DAP-resistant). Additionally, the activity of genes previously associated with DAP resistance was assessed. Materials and Methods: Two MSSA isolates from patient with left-sided endocarditis were analyzed by whole genome sequencing (WGS) and reverse transcription-quantitative real-time PCR (RT-qPCR). The first isolate, DAP-susceptible, was obtained before initiation of treatment and the second isolate, DAP-resistant, was recovered after 4 weeks of DAP therapy. Results: Comparison of complete genomes of DAP-susceptible and its DAP-resistant variant identified two non-synonymous and one synonymous mutations. The non-synonymous mutations consisted of a S829L substitution in mprF and a T331I substitution in vraS. The RT-qPCR experiments revealed an increased expression of vraS, dltA, mprF, and sceD genes in DAP-resistant variant. Strikingly, the expression of dltA and mprF genes was significantly downregulated by DAP. Conclusion: The mprF and vraS genes were previously associated with DAP resistance, however, none of the mutations described in this study had been previously identified and linked to DAP resistance. Moreover, we provide a new insight into the DAP action on S. aureus, in which the expression of key genes in DAP resistance is decreased by the antibiotic.

https://www.ncbi.nlm.nih.gov/pubmed/30459746