Novel Determinants of Antibiotic Resistance: Identification of Mutated Loci in Highly Methicillin-Resistant Subpopulations of Methicillin-Resistant Staphylococcus aureus
Novel Determinants of Antibiotic Resistance: Identification of Mutated Loci in Highly Methicillin-Resistant Subpopulations of Methicillin-Resistant Staphylococcus aureus
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DOI：
10.1128/mbio.01000-13
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发表时间：
2014-03-01
期刊：
影响因子：
6.4
通讯作者：
Tomasz, Alexander
中科院分区：
文献类型：
--
作者：
Dordel, Janina;Kim, Choonkeun;Tomasz, Alexander
我们在耐甲氧西林金黄色葡萄球菌（MRSA）的高度耐药亚群中鉴定了突变基因，这些基因最有可能是β-内酰胺类抗生素作为治疗这些重要病原体的治疗剂的历史性失败的原因。这些亚群是在大多数临床MRSA菌株的生长过程中产生的，包括本文研究的四种历史上早期的MRSA菌株。从高抗性细胞中制备染色体DNA，沿着制备大部分细胞（抗性差的细胞）的DNA，然后进行全基因组测序。在高耐药细胞中，在3个基因间序列和代表广泛功能类别的27个基因中鉴定出突变。这些突变的一个共同特征似乎是它们能够诱导高水平的β-内酰胺耐药性和细菌中耐药蛋白PBP 2A的量增加。这些观察结果符合最近描述的模型，其中MRSA中β-内酰胺抗性表型表达的最终控制因素是RelA介导的严格应答。抑制生长所需的β-内酰胺抗生素的最小浓度）取决于耐甲氧西林金黄色葡萄球菌（MRSA）菌株的抗性蛋白PBP 2A的转录和翻译。在这里，我们描述了一个额外的新的一组遗传决定因素，似乎是必不可少的异常高的耐药水平典型的葡萄球菌亚群，产生独特的低频率在大多数MRSA临床分离株突变位点。我们提出，这些决定因素的突变可以触发诱导的严格的应激反应，这是最近被证明会导致增加的转录/翻译的抗性蛋白PBP 2A在平行的抗性水平的增加。
We identified mutated genes in highly resistant subpopulations of methicillin-resistant Staphylococcus aureus (MRSA) that are most likely responsible for the historic failure of the beta-lactam family of antibiotics as therapeutic agents against these important pathogens. Such subpopulations are produced during growth of most clinical MRSA strains, including the four historically early MRSA isolates studied here. Chromosomal DNA was prepared from the highly resistant cells along with DNA from the majority of cells (poorly resistant cells) followed by full genome sequencing. In the highly resistant cells, mutations were identified in 3 intergenic sequences and 27 genes representing a wide range of functional categories. A common feature of these mutations appears to be their capacity to induce high-level beta-lactam resistance and increased amounts of the resistance protein PBP2A in the bacteria. The observations fit a recently described model in which the ultimate controlling factor of the phenotypic expression of beta-lactam resistance in MRSA is a RelA-mediated stringent response.IMPORTANCE It has been well established that the level of antibiotic resistance (i.e., minimum concentration of a beta-lactam antibiotic needed to inhibit growth) of a methicillin-resistant Staphylococcus aureus (MRSA) strain depends on the transcription and translation of the resistance protein PBP2A. Here we describe mutated loci in an additional novel set of genetic determinants that appear to be essential for the unusually high resistance levels typical of subpopulations of staphylococci that are produced with unique low frequency in most MRSA clinical isolates. We propose that mutations in these determinants can trigger induction of the stringent stress response which was recently shown to cause increased transcription/translation of the resistance protein PBP2A in parallel with the increased level of resistance.