Mutations in the gdpP gene are a clinically relevant mechanism for β-lactam resistance in meticillin-resistant Staphylococcus aureus lacking mec determinants.
Mutations in the gdpP gene are a clinically relevant mechanism for β-lactam resistance in meticillin-resistant Staphylococcus aureus lacking mec determinants.
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gdpP 基因突变是缺乏 mec 决定簇的耐甲氧西林金黄色葡萄球菌中 β-内酰胺耐药的临床相关机制。
DOI：
10.1099/mgen.0.000623
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发表时间：
2021-09
影响因子：
3.9
通讯作者：
Strommenger B
中科院分区：
文献类型：
--
作者：
Sommer A;Fuchs S;Layer F;Schaudinn C;Weber RE;Richard H;Erdmann MB;Laue M;Schuster CF;Werner G;Strommenger B
在金黄色葡萄球菌中，对β-内酰胺酶稳定的β-内酰胺类抗生素的耐药性是由青霉素结合蛋白2a介导的，该蛋白由mecA或其同系物mecB或mecC编码。然而，大量的甲氧西林耐药株缺乏已知的mec基因，因此被称为甲氧西林耐药缺失mec(MRLM)。本研究旨在确定MRLM表型的遗传机制。共有141株MRLM分离株和142例甲氧西林敏感对照纳入本研究。用微量肉汤稀释法测定苯唑西林和头孢西丁的最低抑菌浓度，用聚合酶链式反应排除mec基因的存在。应用比较基因组学和全基因组关联研究(GWAS)方法来确定与MRLM表型相关的遗传多态。研究了这些突变对PBP4的表达以及对细胞形态和生物膜形成的潜在影响。GWAS显示gdpP突变与MRLM表型显著相关。GdpP是一种磷酸二酯酶，参与降解金黄色葡萄球菌中的第二信使环二AMP。共有131株MRLM携带截短、插入或缺失以及氨基酸替换，主要位于GdpP的DHH功能区。我们通过异源互补实验从实验上验证了这些gdpP突变对MRLM表型的贡献。GdpP基因突变对pbp4的转录水平没有影响，但MRLM菌株的细胞尺寸变小。对生物膜形成的影响高度依赖于应变。我们报告gdpP基因突变是耐甲氧西林金黄色葡萄球菌对β-内酰胺类抗生素耐药的临床相关机制。这一观察结果具有特别的临床意义，因为耐甲氧西林金黄色葡萄球菌很容易被错误归类为甲氧西林敏感金黄色葡萄球菌，这可能导致β内酰胺类耐药菌株的不为人知的传播和随后的治疗失败。
In Staphylococcus aureus , resistance to β-lactamase stable β-lactam antibiotics is mediated by the penicillinbinding protein 2a, encoded by mecA or by its homologues mecB or mecC. However, a substantial number of meticillin-resistant isolates lack known mec genes and, thus, are called meticillin resistant lacking mec (MRLM). This study aims to identify the genetic mechanisms underlying the MRLM phenotype. A total of 141 MRLM isolates and 142 meticillin-susceptible controls were included in this study. Oxacillin and cefoxitin minimum inhibitory concentrations were determined by broth microdilution and the presence of mec genes was excluded by PCR. Comparative genomics and a genome-wide association study (GWAS) approach were applied to identify genetic polymorphisms associated with the MRLM phenotype. The potential impact of such mutations on the expression of PBP4, as well as on cell morphology and biofilm formation, was investigated. GWAS revealed that mutations in gdpP were significantly associated with the MRLM phenotype. GdpP is a phosphodiesterase enzyme involved in the degradation of the second messenger cyclic-di-AMP in S. aureus . A total of 131 MRLM isolates carried truncations, insertions or deletions as well as amino acid substitutions, mainly located in the functional DHH-domain of GdpP. We experimentally verified the contribution of these gdpP mutations to the MRLM phenotype by heterologous complementation experiments. The mutations in gdpP had no effect on transcription levels of pbp4; however, cell sizes of MRLM strains were reduced. The impact on biofilm formation was highly strain dependent. We report mutations in gdpP as a clinically relevant mechanism for β-lactam resistance in MRLM isolates. This observation is of particular clinical relevance, since MRLM are easily misclassified as MSSA (meticillin-susceptible S. aureus ), which may lead to unnoticed spread of β-lactam-resistant isolates and subsequent treatment failure.
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影响因子：
14.2
作者：
Croes, S.;Beisser, P. S.;Stobberingh, E. E.
通讯作者：
Stobberingh, E. E.
DOI：
10.1093/jac/dkt418
发表时间：
2014-03
期刊：
The Journal of antimicrobial chemotherapy
影响因子：
--
作者：
Ba X;Harrison EM;Edwards GF;Holden MT;Larsen AR;Petersen A;Skov RL;Peacock SJ;Parkhill J;Paterson GK;Holmes MA
通讯作者：
Holmes MA
影响因子：
4.9
作者：
Chatterjee, Som S.;Chen, Liang;Chambers, Henry F.
通讯作者：
Chambers, Henry F.
DOI：
10.1007/s100960050413
发表时间：
1999-11-01
影响因子：
4.5
作者：
Cuny, C;Pasemann, B;Witte, W
通讯作者：
Witte, W
影响因子：
12.3
作者：
Brynildsrud O;Bohlin J;Scheffer L;Eldholm V
通讯作者：
Eldholm V