Evolution of Multi-Resistance to Vancomycin, Daptomycin, and Linezolid in Methicillin-ResistantStaphylococcus aureusCausing Persistent Bacteremia
Evolution of Multi-Resistance to Vancomycin, Daptomycin, and Linezolid in Methicillin-ResistantStaphylococcus aureusCausing Persistent Bacteremia
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DOI：
10.3389/fmicb.2020.01414
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发表时间：
2020-07-07
影响因子：
5.2
通讯作者：
Shie, Shian-Sen
中科院分区：
文献类型：
--
作者：
Chen, Chih-Jung;Huang, Yhu-Chering;Shie, Shian-Sen
活菌持续感染中的基因组进化是了解耐甲氧西林金黄色葡萄球菌(MRSA)如何适应高抗生素选择压力的宿主环境的关键信息。从1,356天菌血症期间多次抗菌治疗失败的患者身上连续分离出32株对万古霉素(VISA)、达托霉素(DRSA)和/或利奈唑胺(LRSA)递增不敏感的MRSA血液分离株。对所有连续分离的菌株进行全基因组测序(WGS)，以表征进化途径、耐药相关突变及其与抗菌药物治疗的时间关系。基于WGS的系统发育树将这些等基因毒株分为三个主要分支：I(22个分离物)、II(7个分离物)和III(3个分离物)，与第一个分离物相比，它们的中位数(范围)分别为7(1-30)、62(53-65)和118(100-130)个非同义突变。分支I株进一步分为早期和晚期亚支，分别在393.7天和662.5天与分支III株和分支II株共享最近的共同祖先。Clade I和Clade III菌株分别具有较高的VISA(9/22，40.9%)和VISA和DRSA表型(2/3，66.7%)。在8个疗程的利奈唑胺治疗后，Clade II菌株中仅发现对利奈唑胺耐药，包括VISA-DRSA-和-LRSA表型。LRSA表现为小集落变异表型，与23S rRNA V区G2576T突变相关。在多重抗性的进化过程中，鉴定了大量的介导抗性或毒力的可移动元件或等位基因的丢失。然而，基因缺失可能与VISA、DRSA或LRSA表型的发生无关。总之，持续菌血症中的MRSA通过多种途径适应恶劣的宿主环境，包括耐药相关突变和广泛的基因丢失。
The genomic evolutionin vivoin persistent infection was critical information for understanding how methicillin-resistantStaphylococcus aureus(MRSA) was adapted to host environments with high antibiotic selective pressure. Thirty-two successive MRSA blood isolates with incremental non-susceptibility to vancomycin (VISA), daptomycin (DRSA), and/or linezolid (LRSA) were isolated from a patient failing multiple courses of antimicrobial therapy during 1,356 days of bacteremia. Whole genome sequencing (WGS) for all consecutive isolates were conducted to characterize the evolutionary pathways, resistance-associated mutations and their temporal relationship with antimicrobial treatment. The WGS-based phylogeny categorized the isogenic strains into three major clades, I (22 isolates), II (7 isolates), and III (3 isolates), respectively, harboring a median (range) of 7 (1-30), 62 (53-65), and 118 (100-130) non-synonymous mutations when compared to the very first isolate. Clade I strains were further grouped into early and late subclades, which, respectively, shared the most recent common ancestor with Clade III strains at day 393.7 and Clade II strain at day 662.5. Clade I and Clade III strains were characterized, respectively, with high rates of VISA (9/22, 40.9%) and VISA-and-DRSA phenotype (2/3, 66.7%). Linezolid-resistance including VISA-DRSA-and-LRSA phenotype was exclusively identified in Clade II strains after eight courses of linezolid treatment. The LRSA displayed a small colony variant phenotype and were associated with G2576T mutations in domain V region of 23S rRNA. Substantial loss of mobile elements or alleles mediating resistance or virulence were identified during the evolution of multi-resistance. However, the gene loss might not be correlated to the development of VISA, DRSA, or LRSA phenotype. In conclusion, MRSA in persistent bacteremia was adapted to harsh host environment through multiple pathways involving both resistance-associated mutations and extensive gene loss.