来自皮肤和软组织感染的耐甲氧西林金黄色葡萄球菌分离株中碳酸氢钠反应性表型的表型和基因型相关性
Phenotypic and genotypic correlates of the sodium bicarbonate-responsive phenotype among methicillin-resistant Staphylococcus aureus isolates from skin and soft-tissue infections.
作者信息
Ersoy Selvi C, Madrigal Sabrina L, Chen Liang, Mediavilla Jose, Kreiswirth Barry, Flores Evelyn A, Miller Loren G, Xiong Yan Q, Harrison Ewan M, Blane Beth, Peacock Sharon J, Patel Robin, Chambers Henry F, Bayer Arnold S, Proctor Richard A
机构信息
The Lundquist Institute for Biomedical Innovations, Division of Infectious Disease, Harbor-UCLA Medical Center, Torrance, CA, USA; David Geffen School of Medicine, University of California-Los Angeles, Los Angeles, CA, USA.
California State University-Los Angeles, Department of Biological Sciences, Los Angeles, CA, USA.
出版信息
Clin Microbiol Infect. 2025 Apr;31(4):588-593. doi: 10.1016/j.cmi.2024.11.034. Epub 2024 Dec 1.
OBJECTIVES
The objective of this study is to assess the frequency of the novel sodium bicarbonate (NaHCO)-responsive phenotype, wherein clinical methicillin-resistant Staphylococcus aureus (MRSA) isolates are rendered susceptible to standard-of-care β-lactams in the presence of NaHCO, in a collection of 103 clinical U.S. MRSA skin and soft-tissue infection (SSTI) isolates and 22 clinical European SSTI isolates. This study determined the correlation between specific phenotypic and genotypic metrics and the NaHCO-responsive phenotype among U.S. SSTI isolates.
METHODS
Antimicrobial susceptibility testing was performed to determine susceptibility phenotypes. Targeted and whole-genome sequencing with a genome-wide sequence analysis were conducted to identify specific and novel genotypes of interest that may be associated with the NaHCO-responsive phenotype. Gene expression analysis and targeted gene deletion were performed to assess the role of a specific novel genetic locus in the NaHCO-responsive phenotype.
RESULTS
The NaHCO-responsive phenotype was identified in 78/103 U.S. isolates and 4/22 UK isolates to cefazolin (CFZ), and in 17/103 U.S. isolates and 1/22 UK isolates to oxacillin. In U.S. isolates, a significant association was identified between NaHCO-responsiveness to CFZ and: (a) susceptibility to amoxicillin-clavulanate; (b) a specific mecA genotype; (c) clonal complex type 8; and (d) spa type t008. Genome-wide sequence analysis identified single nucleotide polymorphisms (SNPs) in an AraC family regulator (SAUSA300_RS00540) to be exclusively found in NaHCO-non-responsive SSTI strains. In vitro HCO exposures of NaHCO-responsive strains, but not -non-responsive strains, caused >2-fold upregulated expression of this gene. Deletion of this gene rendered NaHCO-responsive strain MRSA 11/11 no longer NaHCO-responsive to CFZ; we have termed this gene the staphylococcal AraC bicarbonate-response regulator.
DISCUSSION
NaHCO-responsiveness is highly associated with clonal complex type 8/spa type t008, a commonly circulating genetic background in North America. The AraC bicarbonate-response regulator, staphylococcal AraC bicarbonate-response regulator, appears to be associated with the mechanism of NaHCO-responsiveness, but more work is needed to verify.
目的
本研究的目的是评估新型碳酸氢钠（NaHCO）反应性表型的频率，即在103株美国临床耐甲氧西林金黄色葡萄球菌（MRSA）皮肤和软组织感染（SSTI）分离株及22株欧洲临床SSTI分离株中，临床MRSA分离株在NaHCO存在下对标准治疗β-内酰胺类药物变得敏感。本研究确定了美国SSTI分离株中特定表型和基因型指标与NaHCO反应性表型之间的相关性。
方法
进行药敏试验以确定药敏表型。进行靶向测序和全基因组测序以及全基因组序列分析，以鉴定可能与NaHCO反应性表型相关的特定和新型感兴趣基因型。进行基因表达分析和靶向基因缺失，以评估特定新型基因座在NaHCO反应性表型中的作用。
结果
在78/103株美国分离株和4/22株英国分离株中鉴定出对头孢唑林（CFZ）的NaHCO反应性表型，在17/103株美国分离株和1/22株英国分离株中鉴定出对苯唑西林的NaHCO反应性表型。在美国分离株中，NaHCO对CFZ的反应性与以下因素之间存在显著关联：（a）对阿莫西林-克拉维酸的敏感性；（b）特定的mecA基因型；（c）克隆复合体8型；（d）spa型t008。全基因组序列分析确定，在一个AraC家族调节因子（SAUSA300_RS00540）中存在单核苷酸多态性（SNP），仅在NaHCO无反应性的SSTI菌株中发现。对NaHCO反应性菌株而非无反应性菌株进行体外HCO暴露，导致该基因表达上调2倍以上。缺失该基因使NaHCO反应性菌株MRSA 11/11对CFZ不再具有NaHCO反应性；我们将该基因命名为葡萄球菌AraC碳酸氢盐反应调节因子。
讨论
NaHCO反应性与克隆复合体8型/spa型t008高度相关，这是北美常见的循环遗传背景。AraC碳酸氢盐反应调节因子，即葡萄球菌AraC碳酸氢盐反应调节因子，似乎与NaHCO反应性机制有关，但需要更多工作来验证。
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