摘要

抗生素耐药性的上升限制了耐甲氧西林葡萄球菌感染的治疗选择。葡萄球菌盒式染色体mec（SCCmec）是一种移动遗传元件，是耐甲氧西林抗性决定簇mecA或mecC基因的唯一载体。抗生素的使用增加了抗生素耐药性的传播，但抗生素促进SCCmec水平传播的机制尚不清楚。在这项研究中，我们证明许多抗生素包括β-内酰胺可以诱导细菌染色体上ccrC1和SCCmec切除的表达。特别是，三种广泛使用的靶向DNA复制和修复的抗生素（磺胺甲恶唑，环丙沙星和甲氧苄氨嘧啶）即使在低浓度（1/8×最小抑制浓度）下也诱导更高水平的ccrC1表达和更高比例的SCCmec切除。通过与ccrC1和ccrAB的启动子区域结合，LexA被鉴定为ccrC1和ccrAB的阻遏物。抗生素诱导后RecA的激活缓解了LexA的抑制作用并增加了ccrC1或ccrAB的表达，因此增加了SCCmec对SCCmec转移的切除频率。这些发现使我们提出了一种机制，通过该机制，抗菌剂可促进mecA基因的水平基因转移并促进耐甲氧西林抗性的传播。

The rise of antimicrobial resistance limits therapeutic options for infections by methicillin-resistant staphylococci. The staphylococcal cassette chromosome mec (SCCmec) is a mobile genetic element as the only carrier of the methicillin-resistance determinants, the mecA or mecC gene. The use of antibiotics increases the spread of antibiotic resistance, but the mechanism by which antibiotics promote horizontal dissemination of SCCmec is largely unknown. In this study, we demonstrate that many antibiotics, including β-lactams, can induce the expression of ccrC1 and SCCmec excision from the bacterial chromosome. In particular, three widely used antibiotics targeting DNA replication and repair (sulfamethoxazole, ciprofloxacin and trimethoprim) induced higher levels of ccrC1 expression and higher rates of SCCmec excision even at low concentrations (1/8 × minimum inhibitory concentration). LexA was identified as a repressor of ccrC1 and ccrAB by binding to the promoter regions of ccrC1 and ccrAB. The activation of RecA after antibiotic induction alleviated the repression by LexA and increased the expression of ccrC1 or ccrAB, consequently increasing the excision frequency of the SCCmec for SCCmec transfer. These findings lead us to propose a mechanism by which antimicrobial agents can promote horizontal gene transfer of the mecA gene and facilitate the spread of methicillin resistance.

https://academic.oup.com/nar/article/45/7/3944/3061129