Department of Pathology and Genomic Medicine, Center for Molecular and Translational Human Infectious Diseases Research, Houston Methodist Research Institute, Houston, Texas, USA.
Houston Methodist Cancer Center, Houston Methodist Hospital, Houston, Texas, USA.
mSphere. 2019 Feb 13;4(1):e00557-18. doi: 10.1128/mSphere.00557-18.
Methicillin-resistant (MRSA) threatens human health in hospital and community settings. The lipopeptide antibiotic daptomycin (DAP) is a frequently used treatment option for MRSA infection. DAP exposure can cause bacterial resistance because mutations are induced in genes implicated in cell membrane and cell wall metabolism. Adaptations aimed at surviving antimicrobial pressure can affect bacterial physiology and modify aptitude and pathogenesis. In this study, clinical DAP-susceptible (DAP) and DAP-resistant (DAP) MRSA isolates were used to investigate associations between DAP resistance and staphylococcal virulence. We previously found that VraSR is a critical sensor of cell membrane/wall homeostasis associated with DAP acquisition during MRSA infection. The present study found that DAP CB1634 and CB5014 MRSA strains with upregulation were less virulent than their susceptible counterparts, CB1631 and CB5013. Differential gene-transcription profile analysis revealed that DAP CB1634 had decreased two-component system expression, virulence factors, and highly suppressed hemolysis activity. Functional genetic analysis performed in DAP CB1634 strains using inactivation followed by gene complementation found that acted as a transcriptional regulator. These results indicated that VraSR has a broad range of regulatory functions. VraSR also appeared to affect DAP adherence to epithelial cells, which would affect DAP strain colonization and survival in the host. The correlation between DAP resistance and decreased virulence was also found in the CB5013 (DAP) and CB5014 (DAP) pair. Taken together, these findings are the first evidence that DAP resistance and MRSA virulence are tightly connected and involve compromised expression of regulatory and virulence determinants. Methicillin-resistant continues to develop resistance to antimicrobials, including those in current clinical use as daptomycin (DAP). Resistance to DAP arises by mutations in cell membrane and cell wall genes and/or upregulation of the two-component VraSR system. However, less is known about the connection between the pathogen and virulence traits during DAP resistance development. We provide new insights into VraSR and its regulatory role for virulence factors during DAP resistance, highlighting coordinated interactions that favor the higher persistence of MRSA DAP-resistant strains in the infected host.
耐甲氧西林金黄色葡萄球菌（MRSA）在医院和社区环境中威胁着人类健康。脂肽类抗生素达托霉素（DAP）是治疗 MRSA 感染的常用药物。DAP 暴露会导致细菌产生耐药性，因为细胞膜和细胞壁代谢相关基因的突变会被诱导。为了在抗菌压力下生存而进行的适应性改变会影响细菌的生理机能并改变其适应能力和发病机制。在这项研究中，使用临床 DAP 敏感（DAP）和 DAP 耐药（DAP）MRSA 分离株来研究 DAP 耐药性与葡萄球菌毒力之间的关系。我们之前发现，VraSR 是一种关键的传感器，可感知与 MRSA 感染期间 DAP 摄取相关的细胞膜/细胞壁动态平衡。本研究发现，上调的 DAP CB1634 和 CB5014 MRSA 菌株比其敏感的对照菌株 CB1631 和 CB5013 毒力更低。差异基因转录谱分析显示，DAP CB1634 的双组分系统表达、毒力因子减少，且溶血活性受到高度抑制。在 DAP CB1634 菌株中使用失活和基因互补进行的功能遗传分析发现，VraSR 充当转录调节剂。这些结果表明，VraSR 具有广泛的调节功能。VraSR 似乎还会影响 DAP 对上皮细胞的附着，这将影响 DAP 菌株在宿主中的定植和存活。在 CB5013（DAP）和 CB5014（DAP）对中也发现了 DAP 耐药性和降低的毒力之间的相关性。总之，这些发现首次证明 DAP 耐药性和 MRSA 毒力之间存在紧密联系，涉及到调节因子和毒力决定因素表达的受损。耐甲氧西林金黄色葡萄球菌（MRSA）继续对包括达托霉素（DAP）在内的目前临床使用的抗生素产生耐药性。DAP 耐药性是通过细胞膜和细胞壁基因的突变和/或双组分 VraSR 系统的上调而产生的。然而，对于 DAP 耐药性发展过程中病原体与毒力特征之间的联系了解较少。我们提供了关于 VraSR 及其在 DAP 耐药性期间对毒力因子的调节作用的新见解，突出了有利于更高比例的 MRSA DAP 耐药菌株在感染宿主中持续存在的协调相互作用。
