Li Yi, Berti Andrew D, Abdelhady Wessam, Xiong Yan Q
The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA 90502, USA.
Department of Pharmacy Practice, Wayne State University College of Pharmacy and Health Sciences, Detroit, MI 48201, USA.
Antibiotics (Basel). 2025 Feb 13;14(2):191. doi: 10.3390/antibiotics14020191.
Persistent methicillin-resistant (MRSA) endovascular infections present a significant clinical therapeutic challenge. Prophages are increasingly recognized as important genetic factors influencing the pathogenicity of , yet their role in antibiotic persistence in MRSA remains underexplored. Our previous work demonstrated that prophage ϕSA169 promotes vancomycin (VAN) persistence in an experimental model of endocarditis caused by MRSA strains with a clonal complex (CC) 45 genetic background. However, it is unknown whether this persistence-promoting effect of ϕSA169 extends to other clinically relevant MRSA lineages. This study aims to elucidate the role of ϕSA169 in influencing VAN persistence across diverse MRSA genetic backgrounds. A pilot analysis of clinical data suggested that patients infected by MRSA containing ϕSA169-like prophage appear to have worse clinical outcomes. Thus, we lysogenized representative clinical resolving bacteremia (RB) MRSA strains with ϕSA169 and evaluated phenotypes closely associated with VAN persistence, including VAN susceptibility, biofilm formation, and the efficacy of VAN treatment in an experimental infective endocarditis (IE) model. Each ϕSA169 lysogenic strain was compared to its isogenic MRSA parental counterpart. ϕSA169 lysogeny significantly promotes biofilm formation and enhances survival to VAN exposure under human-mimicking conditions for RB strains from CC5 and CC30. ϕSA169 lysogeny significantly reduces VAN effectiveness in the IE model due to RB lysogen from CC5 despite no detectable impact on VAN MICs. These results indicate that ϕSA169 promotes VAN persistence across clonal backgrounds, likely through biofilm formation and VAN tolerance. Targeting prophage could provide new strategies to combat persistent MRSA infections.
持续性耐甲氧西林金黄色葡萄球菌（MRSA）血管内感染带来了重大的临床治疗挑战。原噬菌体越来越被认为是影响致病性的重要遗传因素，但其在MRSA抗生素持续性方面的作用仍未得到充分探索。我们之前的研究表明，原噬菌体ϕSA169在由具有克隆复合体（CC）45遗传背景的MRSA菌株引起的心内膜炎实验模型中促进万古霉素（VAN）持续性。然而，尚不清楚ϕSA169的这种促进持续性的作用是否扩展到其他临床相关的MRSA谱系。本研究旨在阐明ϕSA169在不同MRSA遗传背景下影响VAN持续性中的作用。对临床数据的初步分析表明，感染含有ϕSA169样原噬菌体的MRSA患者似乎临床结局更差。因此，我们用ϕSA169使具有代表性的临床治愈菌血症（RB）MRSA菌株溶原化，并在实验性感染性心内膜炎（IE）模型中评估与VAN持续性密切相关的表型，包括VAN敏感性、生物膜形成以及VAN治疗效果。将每个ϕSA169溶原性菌株与其同基因的MRSA亲本菌株进行比较。对于来自CC5和CC30的RB菌株，ϕSA169溶原化显著促进生物膜形成并增强在模拟人体条件下对VAN暴露的存活能力。尽管对VAN最低抑菌浓度没有可检测到的影响，但由于来自CC5的RB溶原菌，ϕSA169溶原化在IE模型中显著降低VAN有效性。这些结果表明，ϕSA169可能通过生物膜形成和VAN耐受性在不同克隆背景下促进VAN持续性。靶向原噬菌体可为对抗持续性MRSA感染提供新策略。
