Aedo Sandra, Tomasz Alexander
Laboratory of Microbiology & Infectious Diseases, The Rockefeller University, New York, New York, USA.
Laboratory of Microbiology & Infectious Diseases, The Rockefeller University, New York, New York, USA
Antimicrob Agents Chemother. 2016 Mar 25;60(4):2311-7. doi: 10.1128/AAC.02697-15. Print 2016 Apr.
Resistance to beta-lactam antibiotics in methicillin-resistantStaphylococcus aureus(MRSA) requires the presence of an acquired genetic determinant,mecAormecC, which encode penicillin-binding protein PBP2A or PBP2A', respectively. Although all MRSA strains share a mechanism of resistance, the phenotypic expression of beta-lactam resistance shows considerable strain-to-strain variation. The stringent stress response, a stress response that results from nutrient limitation, was shown to play a key role in determining the resistance level of an MRSA strain. In the present study, we validated the impact of the stringent stress response on transcription and translation ofmecAin the MRSA clinical isolate strain N315, which also carries known regulatory genes (mecI/mecR1/mecR2andblaI/blaR1) formecAtranscription. We showed that the impact of the stringent stress response on the resistance level may be restricted to beta-lactam resistance based on a "foreign" determinant such asmecA, as opposed to resistance based on mutations in the nativeS. aureusdeterminantpbpB(encoding PBP2). Our observations demonstrate that high-level resistance mediated by the stringent stress response follows the current model of beta-lactam resistance in which the native PBP2 protein is also essential for expression of the resistance phenotype. We also show that theStaphylococcus sciuri pbpDgene (also calledmecAI), the putative evolutionary precursor ofmecA, confers oxacillin resistance in anS. aureusstrain, generating a heterogeneous phenotype that can be converted to high and homogenous resistance by induction of the stringent stress response in the bacteria.
耐甲氧西林金黄色葡萄球菌（MRSA）对β-内酰胺类抗生素的耐药性需要存在一种获得性遗传决定因素，即mecA或mecC，它们分别编码青霉素结合蛋白PBP2A或PBP2A'。尽管所有MRSA菌株都有共同的耐药机制，但β-内酰胺耐药性的表型表达在菌株间存在相当大的差异。严格应激反应是由营养限制引起的一种应激反应，已被证明在决定MRSA菌株的耐药水平中起关键作用。在本研究中，我们验证了严格应激反应对MRSA临床分离株N315中mecA转录和翻译的影响，该菌株还携带已知的mecA转录调控基因（mecI/mecR1/mecR2和blaI/blaR1）。我们表明，严格应激反应对耐药水平的影响可能仅限于基于“外来”决定因素（如mecA）的β-内酰胺耐药性，而不是基于金黄色葡萄球菌天然决定因素pbpB（编码PBP2）突变的耐药性。我们的观察结果表明，由严格应激反应介导的高水平耐药性遵循当前的β-内酰胺耐药模型，其中天然PBP2蛋白对于耐药表型的表达也至关重要。我们还表明，松鼠葡萄球菌pbpD基因（也称为mecAI）是mecA的推定进化前体，可在金黄色葡萄球菌菌株中赋予对苯唑西林的耐药性，产生一种异质表型，通过诱导细菌中的严格应激反应可将其转化为高且均匀的耐药性。
