PDF(Pubmed)
Abstract：
Methicillin-resistant Staphylococcus aureus (MRSA) strains are a major challenge for clinicians due, in part, to their resistance to most β-lactams, the first-line treatment for methicillin-susceptible S. aureus. A phenotype termed \"NaHCO3-responsiveness\" has been identified, wherein many clinical MRSA isolates are rendered susceptible to standard-of-care β-lactams in the presence of physiologically relevant concentrations of NaHCO3, in vitro and ex vivo; moreover, such \"NaHCO3-responsive\" isolates can be effectively cleared by β-lactams from target tissues in experimental infective endocarditis (IE). One mechanistic impact of NaHCO3 exposure on NaHCO3-responsive MRSA is to repress WTA synthesis. This NaHCO3 effect mimics the phenotype of tarO-deficient MRSA, including sensitization to the PBP2-targeting β-lactam, cefuroxime (CFX). Herein, we further investigated the impacts of NaHCO3 exposure on CFX susceptibility in the presence and absence of a WTA synthesis inhibitor, ticlopidine (TCP), in a collection of clinical MRSA isolates from skin and soft tissue infections (SSTI) and bloodstream infections (BSI). NaHCO3 and/or TCP enhanced susceptibility to CFX in vitro, by both minimum inhibitor concentration (MIC) and time-kill assays, as well as in an ex vivo simulated endocarditis vegetations (SEV) model, in NaHCO3-responsive MRSA. Furthermore, in experimental IE (presumably in the presence of endogenous NaHCO3), pre-exposure to TCP prior to infection sensitized the NaHCO3-responsive MRSA strain (but not the non-responsive strain) to enhanced clearances by CFX in target tissues. These data support the notion that NaHCO3 is acting similarly to WTA synthesis inhibitors, and that such inhibitors have potential translational applications in the treatment of certain MRSA strains in conjunction with specific β-lactam agents.
摘要：
耐甲氧西林金黄色葡萄球菌（MRSA）菌株是临床医生面临的主要挑战，在某种程度上,它们对大多数β-内酰胺的抗性，甲氧西林敏感型金黄色葡萄球菌的一线治疗。已鉴定出一种称为“NaHCO3反应性”的表型，其中许多临床MRSA分离株在存在生理相关浓度的NaHCO3的情况下在体外和离体对标准护理β-内酰胺敏感;此外,在实验性感染性心内膜炎（IE）中，β-内酰胺可以有效地从靶组织中清除此类“NaHCO3反应性”分离株。NaHCO3暴露对NaHCO3响应性MRSA的一个机械影响是抑制WTA合成。这种NaHCO3效应模拟了tarO缺陷型MRSA的表型，包括对PBP2靶向β-内酰胺的致敏，头孢呋辛（CFX）。在这里，我们进一步研究了在存在和不存在WTA合成抑制剂的情况下，NaHCO3暴露对CFX敏感性的影响，噻氯匹定（TCP），在皮肤和软组织感染（SSTI）和血流感染（BSI）的临床MRSA分离株的集合中。NaHCO3和/或TCP在体外增强了对CFX的敏感性，通过最小抑制剂浓度(MIC)和时间杀伤测定，以及在离体模拟心内膜炎植被（SEV）模型中，在NaHCO3反应性MRSA中。此外，在实验IE中(可能存在内源性NaHCO3)，感染前预先暴露于TCP使NaHCO3反应性MRSA菌株（但非反应性菌株）敏感，以增强CFX在靶组织中的清除。这些数据支持以下观点：NaHCO3的作用类似于WTA合成抑制剂，并且这些抑制剂在与特定β-内酰胺试剂联合治疗某些MRSA菌株中具有潜在的翻译应用。
