Si Lizhen, Gu Jing, Wen Mi, Wang Ruiqi, Fleming Joy, Li Jinyue, Xu Jintian, Bi Lijun, Deng Jiaoyu
Key Laboratory of Special Pathogens and Biosafety, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, China.
University of Chinese Academy of Sciences, Beijing, China.
Front Microbiol. 2021 Sep 27;12:698468. doi: 10.3389/fmicb.2021.698468. eCollection 2021.
Folates are required for the biosynthesis of purines, thymine, methionine, glycine, and pantothenic acid, key metabolites that bacterial cells cannot survive without. Sulfonamides, which inhibit bacterial folate biosynthesis and are generally considered as bacteriostats, have been extensively used as broad-spectrum antimicrobials for decades. Here we show that, deleting in and other bacterial species converted sulfamethoxazole from a bacteriostat into a bactericide. Not as previously assumed, the bactericidal effect of SMX was not caused by thymine deficiency. When ∆ was treated with SMX, reactive oxygen species and ferrous ion accumulated inside the bacterial cells, which caused extensive DNA double-strand breaks without the involvement of incomplete base excision repair. In addition, sulfamethoxazole showed bactericidal effect against O157 ∆ in mice, suggesting the possibility of designing new potentiators for sulfonamides targeting RelA. Thus, our study uncovered the previously unknown bactericidal effects of sulfonamides, which advances our understanding of their mechanisms of action, and will facilitate the designing of new potentiators for them.
叶酸是嘌呤、胸腺嘧啶、蛋氨酸、甘氨酸和泛酸生物合成所必需的，这些关键代谢产物是细菌细胞赖以生存的物质。磺胺类药物可抑制细菌叶酸的生物合成，通常被视为抑菌剂，几十年来一直被广泛用作广谱抗菌药物。在此我们表明，在大肠杆菌及其他细菌物种中缺失RelA可将磺胺甲恶唑从抑菌剂转变为杀菌剂。与之前的假设不同，磺胺甲恶唑的杀菌作用并非由胸腺嘧啶缺乏引起。当用磺胺甲恶唑处理RelA缺失的大肠杆菌时，活性氧和亚铁离子在细菌细胞内积累，这导致了广泛的DNA双链断裂，且未涉及不完全碱基切除修复。此外，磺胺甲恶唑在小鼠体内对O157 RelA缺失菌株显示出杀菌作用，这表明有可能设计出针对RelA的磺胺类药物新增效剂。因此，我们的研究揭示了磺胺类药物此前未知的杀菌作用，这增进了我们对其作用机制的理解，并将有助于为它们设计新的增效剂。
