Multiple pathways of cross-resistance to glycopeptides and daptomycin in persistent MRSA bacteraemia
Multiple pathways of cross-resistance to glycopeptides and daptomycin in persistent MRSA bacteraemia
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DOI：
10.1093/jac/dkv225
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发表时间：
2015-11-01
影响因子：
5.2
通讯作者：
Chiu, Cheng-Hsu
中科院分区：
文献类型：
--
作者：
Chen, Chih-Jung;Huang, Yhu-Chering;Chiu, Cheng-Hsu
背景：在持续菌血症期间，MRSA 对糖肽和达托霉素不敏感的发展已成为重大的治疗挑战。然而，双重耐药的体内进化和机制仍未完全了解。方法：从化疗失败的菌血症患者中连续回收一系列对糖肽和达托霉素不敏感的MRSA血液分离株。然后通过同基因菌株的全基因组测序追踪从糖肽和达托霉素敏感表型转化为万古霉素中间金黄色葡萄球菌（VISA）和达托霉素抗性金黄色葡萄球菌（DRSA）表型的进化途径。结果：在该菌株的发育过程中，总共鉴定了 6 个非同义突变和 3 条进化途径。 VISA/DRSA 表型。第一条途径涉及两个进化步骤，首先将 1 bp 插入 yycH，然后在 mprF (S295L) 中进行功能获得性点突变。这两种突变与达托霉素/万古霉素异质抗性和 VISA/DRSA 表型的全面发展相关。第二条途径涉及 yycH 中的 11 bp 缺失突变和两个基因的点突变，与 VISA 表型的发展和达托霉素异质抗性相关。在第三条途径中鉴定出 mprF (S295L) 突变和 yycH 中 5 bp 缺失突变，并对应于向完整 VISA/DRSA 表型的转化。 yycH突变导致YycH提前终止，长度可变。结论：涉及yycH和mprF的多种进化途径可以同时进行，并可能在抗生素选择压力下持续MRSA菌血症期间介导对糖肽和达托霉素的交叉耐药性。
Background: The development of non-susceptibility to glycopeptides and daptomycin in MRSA during persistent bacteraemia has become a significant therapeutic challenge. However, the in vivo evolution and mechanism of the dual resistance have remained incompletely understood.Methods: A series of MRSA blood isolates with incremental non-susceptibility to glycopeptides and daptomycin were consecutively recovered from a bacteraemic patient who was failing chemotherapy. The evolutionary pathways during conversion from a glycopeptide-and daptomycin-susceptible phenotype into a vancomycin-intermediate Staphylococcus aureus (VISA) and a daptomycin-resistant S. aureus (DRSA) phenotype were then traced by WGS of the isogenic strains.Results: A total of six non-synonymous mutations and three evolutionary pathways were identified during the development of the VISA/DRSA phenotype. The first pathway involved two steps of evolution, with an initial 1 bp insertion into yycH and a subsequent gain-in-function point mutation in mprF (S295L). The two mutations were correlated with heteroresistance to daptomycin/vancomycin and full development of the VISA/DRSA phenotype. The second pathway involved an 11 bp deletion mutation in yycH and point mutations at two genes, correlating with the development of the VISA phenotype and heteroresistance to daptomycin. Mutation in mprF (S295L) and a 5 bp deletion mutation in yycH were identified in the third pathway and corresponded to conversion into the full VISA/DRSA phenotype. The mutations in yycH resulted in premature terminations of YycH with variable lengths.Conclusions: Multiple evolutionary pathways involving yycH and mprF can proceed simultaneously and may mediate cross-resistance to glycopeptides and daptomycin during persistent MRSA bacteraemia under antibiotic selective pressure.