Department of Microbial Pathogenesis, School of Dentistry, University of Maryland Baltimore, Baltimore, Maryland, USA.
Institute of Marine and Environmental Technology (IMET), Baltimore, Maryland, USA.
mBio. 2024 May 8;15(5):e0288923. doi: 10.1128/mbio.02889-23. Epub 2024 Mar 26.
Infections caused by are a leading cause of mortality worldwide. infections caused by methicillin-resistant (MRSA) are particularly difficult to treat due to their resistance to next-generation β-lactams (NGBs) such as methicillin, nafcillin, and oxacillin. Resistance to NGBs, which is alternatively known as broad-spectrum β-lactam resistance, is classically mediated by PBP2a, a penicillin-binding protein encoded by (or ) in MRSA. Thus, presence of genes among spp. serves as the predictor of resistance to NGBs and facilitates determination of the proper therapeutic strategy for a staphylococcal infection. Although far less appreciated, -deficient strains can also exhibit NGB resistance. These strains, which are collectively termed as methicillin-resistant lacking (MRLM), are currently being identified in increasing numbers among natural resistant isolates of . The mechanism/s through which MRLMs produce resistance to NGBs remains unknown. In this study, we demonstrate that mutations that alter PBP4 and GdpP functions, which are often present among MRLMs, can synergistically mediate resistance to NGBs. Furthermore, our results unravel that this novel mechanism potentially enables MRLMs to produce resistance toward NGBs at levels comparable to those of MRSAs. Our study provides a fresh new perspective about alternative mechanisms of NGB resistance, challenging our current overall understanding of high-level, broad-spectrum β-lactam resistance in . It thus suggests reconsideration of the current approach toward diagnosis and treatment of β-lactam-resistant infections.
In , high-level, broad-spectrum resistance to β-lactams such as methicillin, also referred to as methicillin resistance, is largely attributed to . This study demonstrates that strains that lack but contain mutations that functionally alter PBP4 and GdpP can also mediate high-level, broad-spectrum resistance to β-lactams. Resistance brought about by the synergistic action of functionally altered PBP4 and GdpP was phenotypically comparable to that displayed by , as seen by increased bacterial survival in the presence of β-lactams. An analysis of mutations detected in naturally isolated strains of revealed that a significant proportion of them had similar and GDEF omain rotein containing hosphodiesterase () mutations, making this study clinically significant. This study not only identifies important players of non-classical mechanisms of β-lactam resistance but also indicates reconsideration of current clinical diagnosis and treatment protocols of infections.
由 引起的感染是全球范围内导致死亡的主要原因。由于耐甲氧西林金黄色葡萄球菌（MRSA）引起的感染对下一代β-内酰胺类药物（NGBs）如甲氧西林、萘夫西林和苯唑西林具有耐药性，因此特别难以治疗。对 NGBs 的耐药性，也称为广谱β-内酰胺耐药性，经典上由青霉素结合蛋白 2a（PBP2a）介导，PBP2a 是由 （或 ）编码的耐甲氧西林金黄色葡萄球菌中的一种青霉素结合蛋白。因此， spp.中 基因的存在可作为对 NGB 耐药性的预测因子，并有助于确定葡萄球菌感染的适当治疗策略。尽管远未被充分认识，但缺乏 （PBP4）的 株也可表现出对 NGB 的耐药性。这些菌株统称为缺乏 （PBP4）的耐甲氧西林金黄色葡萄球菌（MRLM），目前在天然耐药的 株中越来越多地被发现。产生 NGB 耐药性的 MRLM 机制尚不清楚。在这项研究中，我们证明了改变 PBP4 和 GdpP 功能的突变，这些突变经常存在于 MRLM 中，可协同介导对 NGB 的耐药性。此外，我们的结果揭示了这种新机制可能使 MRLM 产生对 NGB 的耐药性，其水平可与耐甲氧西林金黄色葡萄球菌相媲美。我们的研究提供了关于 NGB 耐药性替代机制的新视角，挑战了我们对 高水平广谱β-内酰胺耐药性的总体认识。因此，建议重新考虑当前针对β-内酰胺耐药 感染的诊断和治疗方法。
在 中，对β-内酰胺类药物（如甲氧西林）的高水平广谱耐药性，也称为耐甲氧西林，主要归因于 。这项研究表明，缺乏 但含有可改变 PBP4 和 GdpP 功能的突变的 株也可以介导对β-内酰胺类药物的高水平广谱耐药性。功能改变的 PBP4 和 GdpP 的协同作用引起的耐药性在表型上与 相当，这表现在β-内酰胺存在时细菌存活增加。对天然分离的 株中检测到的突变的分析表明，其中相当一部分具有相似的 GDEF 结构域蛋白磷酸二酯酶（）突变，这使得该研究具有临床意义。这项研究不仅确定了非经典β-内酰胺耐药机制的重要参与者，还表明需要重新考虑当前针对 感染的临床诊断和治疗方案。
