The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, California, USA.
Department of Microbiology & Immunology, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire, USA.
Microbiol Spectr. 2023 Aug 17;11(4):e0060023. doi: 10.1128/spectrum.00600-23. Epub 2023 Jun 26.
Persistent methicillin-resistant Staphylococcus aureus (MRSA) endovascular infections represent a serious public health threat. We recently demonstrated that the presence of a novel prophage ϕSA169 was associated with vancomycin (VAN) treatment failure in experimental MRSA endocarditis. In this study, we assessed the role of a ϕSA169 gene, ϕ80α_ (), in VAN-persistent outcome using isogenic MRSA strain sets. Of note, Gp05 significantly influences the intersection of MRSA virulence factors, host immune responses, and antibiotic treatment efficacy, including the following: (i) activity of the significant energy-yielding metabolic pathway (e.g., tricarboxylic acid cycle); (ii) carotenoid pigment production; (iii) (p)ppGpp (guanosine tetra- and pentaphosphate) production, which activates the stringent response and subsequent downstream functional factors (e.g., phenol-soluble modulins and polymorphonuclear neutrophil bactericidal activity); and (iv) persistence to VAN treatment in an experimental infective endocarditis model. These data suggest that Gp05 is a significant virulence factor which contributes to the persistent outcomes in MRSA endovascular infection by multiple pathways. Persistent endovascular infections are often caused by MRSA strains that are susceptible to anti-MRSA antibiotics by CLSI breakpoints. Thus, the persistent outcome represents a unique variant of traditional antibiotic resistance mechanisms and a significant therapeutic challenge. Prophage, a critical mobile genetic element carried by most MRSA isolates, provides their bacterial host with metabolic advantages and resistance mechanisms. However, how prophage-encoded virulence factors interact with the host defense system and antibiotics, driving the persistent outcome, is not well known. In the current study, we demonstrated that a novel prophage gene, , significantly impacts tricarboxylic acid cycle activity, stringent response, and pigmentation, as well as vancomycin treatment outcome in an experimental endocarditis model using isogenic overexpression and chromosomal deletion mutant MRSA strain sets. The findings significantly advance our understanding of the role of Gp05 in persistent MRSA endovascular infection and provide a potential target for development of novel drugs against these life-threatening infections.
耐甲氧西林金黄色葡萄球菌（MRSA）持续性血管内感染是严重的公共卫生威胁。我们最近证明，新型前噬菌体ϕSA169 的存在与实验性 MRSA 心内膜炎中万古霉素（VAN）治疗失败有关。在这项研究中，我们使用同源性 MRSA 菌株集评估了 ϕSA169 基因 ϕ80α_() 在 VAN 持续性结果中的作用。值得注意的是，Gp05 显著影响 MRSA 毒力因子、宿主免疫反应和抗生素治疗效果的交集，包括以下方面：（i）重要能量产生代谢途径（如三羧酸循环）的活性；（ii）类胡萝卜素色素的产生；（iii）（p）ppGpp（鸟苷四和五磷酸）的产生，激活严格反应和随后的下游功能因子（如酚可溶性调节素和多形核中性粒细胞杀菌活性）；和（iv）在实验性感染性心内膜炎模型中对 VAN 治疗的持久性。这些数据表明，Gp05 是一个重要的毒力因子，通过多种途径导致 MRSA 血管内感染的持续性结果。持续性血管内感染通常由 CLSI 断点敏感的抗-MRSA 抗生素的 MRSA 菌株引起。因此，持续性结果代表了传统抗生素耐药机制的独特变体，也是一个重大的治疗挑战。前噬菌体是大多数 MRSA 分离株携带的关键移动遗传元件，为其细菌宿主提供代谢优势和耐药机制。然而，前噬菌体编码的毒力因子如何与宿主防御系统和抗生素相互作用，导致持续性结果，目前还不清楚。在本研究中，我们使用同源性过表达和染色体缺失突变 MRSA 菌株集，在实验性心内膜炎模型中证明，一种新型前噬菌体基因ϕ80α_() 显著影响三羧酸循环活性、严格反应和色素沉着以及万古霉素治疗结果。这些发现极大地促进了我们对 Gp05 在持续性 MRSA 血管内感染中的作用的理解，并为开发针对这些危及生命的感染的新型药物提供了一个潜在的靶点。
