Liu Pilong, Wu Zhaowei, Xue Huping, Zhao Xin
College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi 712100, China.
Department of Animal Science, McGill University, Ste Anne de Bellevue, Quebec H9X3V9, Canada.
Nucleic Acids Res. 2017 Apr 20;45(7):3944-3952. doi: 10.1093/nar/gkx153.
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.
抗菌药物耐药性的增加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）作为甲氧西林耐药决定因子mecA或mecC基因的唯一载体，是一种可移动遗传元件。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水平传播的机制很大程度上尚不清楚。在本研究中，我们证明许多抗生素，包括β-内酰胺类抗生素，可诱导ccrC1表达及SCCmec从细菌染色体上切除。特别是三种广泛用于靶向DNA复制和修复的抗生素（磺胺甲恶唑、环丙沙星和甲氧苄啶），即使在低浓度（1/8×最低抑菌浓度）下也能诱导更高水平的ccrC1表达和更高的SCCmec切除率。LexA被确定为通过结合ccrC1和ccrAB的启动子区域来抑制ccrC1和ccrAB。抗生素诱导后RecA的激活减轻了LexA的抑制作用，增加了ccrC1或ccrAB的表达，从而提高了SCCmec转移时SCCmec的切除频率。这些发现使我们提出一种机制，通过该机制抗菌药物可促进mecA基因的水平基因转移并促进甲氧西林耐药性的传播。
