Department of Clinical Laboratory, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China.
Department of Clinical Laboratory, The First Affiliated Hospital of Wannan Medical College (Yijishan Hospital of Wannan Medical College), Wuhu, China.
Antimicrob Agents Chemother. 2024 Mar 6;68(3):e0089323. doi: 10.1128/aac.00893-23. Epub 2024 Jan 23.
is an important human pathogen and vancomycin is widely used for the treatment of infections. The global regulator is known as a well-described virulence regulator. Previous studies have found that -dysfunction strains are more likely to develop into vancomycin-resistant strains, but the mechanism for this phenomenon remains unknown. VraSR is a two-component regulatory system related to vancomycin resistance. In this study, we found that the expression levels of were higher in -dysfunction clinical strains than in the -functional strains. We knocked out in a clinical strain, and quantitative reverse transcription PCR and β-galactosidase activity assays revealed that repressed transcription of . After vancomycin exposures, population analysis revealed larger subpopulations displaying reduced susceptibility in knockout strain compared with wild-type strain, and this pattern was also observed in -dysfunction clinical strains compared with the -functional strains. Electrophoretic mobility experiment demonstrated binding of purified AgrA to the promoter region of . In conclusion, our results indicated that the loss of function in may contribute to the evolution of reduced vancomycin susceptibility through the downregulation of .
是一种重要的人类病原体，万古霉素被广泛用于治疗 感染。全局调控子 是一种众所周知的毒力调控子。先前的研究发现，-功能失调菌株更有可能发展为万古霉素耐药菌株，但这种现象的机制尚不清楚。VraSR 是一种与万古霉素耐药性相关的双组分调节系统。在这项研究中，我们发现 -功能失调的临床菌株中的 表达水平高于 -功能菌株。我们在临床菌株中敲除了 ，定量逆转录 PCR 和 β-半乳糖苷酶活性测定显示 抑制了 的转录。万古霉素暴露后，群体分析显示，与野生型菌株相比， 敲除菌株中显示出较低药物敏感性的亚群更大，在 -功能失调的临床菌株中也观察到了这种模式，与 -功能菌株相比。电泳迁移实验证明了纯化的 AgrA 与 的启动子区域结合。总之，我们的结果表明， 通过下调 ， 功能丧失可能导致万古霉素敏感性降低的进化。
