A Nonclassical Mechanism of β-Lactam Resistance in Methicillin-Resistant Staphylococcus aureus and Its Effect on Virulence.
A Nonclassical Mechanism of β-Lactam Resistance in Methicillin-Resistant Staphylococcus aureus and Its Effect on Virulence.
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DOI：
10.1128/spectrum.02284-22
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发表时间：
2022-12-21
影响因子：
3.7
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中科院分区：
文献类型：
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耐甲氧西林金黄色葡萄球菌（MRSA）是一组对β-内酰胺类抗生素具有耐药性的致病菌，这一特性归因于mecA基因。最近的研究报道，与pbp 4的启动子区域相关的突变表现出高水平的β-内酰胺耐药性，表明PBP 4作为β-内酰胺耐药性的重要非mecA介导剂的作用。pbp 4启动子相关突变已在有或无mecA的菌株中检测到。我们先前在缺乏mecA的菌株中进行的研究描述了pbp 4启动子相关突变导致PBP 4过表达和β-内酰胺抗性。在这项研究中，通过在MRSA菌株的基因组中引入各种pbp 4启动子相关突变，我们证明了PBP 4过表达可以补充S.金黄色葡萄球菌，并可导致β-内酰胺耐药性增加。pbp 4的启动子和调控区与编码多药输出蛋白的差异转录基因abcA共享。我们证明了启动子突变引起pbp 4的上调和abcA的下调，证实了耐药表型与PBP 4过表达相关。PBP 4也与葡萄球菌的发病机制有关，但其确切作用仍不清楚。使用秀丽隐杆线虫模型，我们证明了PBP 4表达增加的菌株比野生型菌株毒性更低，表明通过PBP 4介导的β-内酰胺抗性可能以毒性为代价。重要性我们的研究表明PBP 4不仅在先前证明的甲氧西林敏感金黄色葡萄球菌（MSSA）背景菌株中而且在MRSA菌株中成为β-内酰胺抗性的重要介体的能力。当一起存在时，PBP 2a和PBP 4过表达可产生增加水平的β-内酰胺抗性，导致治疗并发症。因此，这项研究表明在临床环境中监测PBP 4相关耐药性的重要性，以及了解相关耐药性的机制基础，以便开发针对PBP 4的治疗方法。本研究还表明，S.具有增加的PBP 4表达的金黄色葡萄球菌菌株的致病性较低，提供了关于PBP 4在S.金黄色葡萄球菌耐药性和致病机制。
Methicillin-resistant Staphylococcus aureus (MRSA) is a group of pathogenic bacteria that are infamously resistant to β-lactam antibiotics, a property attributed to the mecA gene. Recent studies have reported that mutations associated with the promoter region of pbp4 demonstrated high levels of β-lactam resistance, suggesting the role of PBP4 as an important non-mecA mediator of β-lactam resistance. The pbp4-promoter-associated mutations have been detected in strains with or without mecA. Our previous studies that were carried out in strains devoid of mecA described that pbp4-promoter-associated mutations lead to PBP4 overexpression and β-lactam resistance. In this study, by introducing various pbp4-promoter-associated mutations in the genome of a MRSA strain, we demonstrate that PBP4 overexpression can supplement mecA-associated resistance in S. aureus and can lead to increased β-lactam resistance. The promoter and regulatory region of pbp4 is shared with a divergently transcribed gene, abcA, which encodes a multidrug exporter. We demonstrate that the promoter mutations caused an upregulation of pbp4 and downregulation of abcA, confirming that the resistant phenotype is associated with PBP4 overexpression. PBP4 has also been associated with staphylococcal pathogenesis, however, its exact role remains unclear. Using a Caenorhabditis elegans model, we demonstrate that strains having increased PBP4 expression are less virulent than wild-type strains, suggesting that β-lactam resistance mediated via PBP4 likely comes at the cost of virulence. IMPORTANCE Our study demonstrates the ability of PBP4 to be an important mediator of β-lactam resistance in not only methicillin-susceptible Staphylococcus aureus (MSSA) background strains as previously demonstrated but also in MRSA strains. When present together, PBP2a and PBP4 overexpression can produce increased levels of β-lactam resistance, causing complications in treatment. Thus, this study suggests the importance of monitoring PBP4-associated resistance in clinical settings, as well as understanding the mechanistic basis of associated resistance, so that treatments targeting PBP4 may be developed. This study also demonstrates that S. aureus strains with increased PBP4 expression are less pathogenic, providing important hints about the role of PBP4 in S. aureus resistance and pathogenesis.
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金黄色葡萄球菌菌血症的临床管理：评论。
影响因子：
120.7
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Holland, Thomas L.;Arnold, Christopher;Fowler, Vance G., Jr.
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