Promoter regulatory mode evolution enhances the high multidrug resistance of tmexCD1-toprJ1

• Published in: mBio Vol. 15; no. 5; p. e0021824
• Main Authors: Wang, Chengzhen, Yang, Jun, Xu, Zeling, Lv, Luchao, Chen, Sheng, Hong, Mei, Liu, Jian-Hua
• Format: Journal Article
• Language: English
• Published: United States American Society for Microbiology 08.05.2024
• Subjects: Anti-Bacterial Agents - pharmacology; antibiotic resistance; Antimicrobial Chemotherapy; Bacterial Proteins - genetics; Bacterial Proteins - metabolism; Drug Resistance, Multiple, Bacterial - genetics; Escherichia coli - drug effects; Escherichia coli - genetics; Escherichia coli - metabolism; evolution; Evolution, Molecular; Gene Expression Regulation, Bacterial; gene regulation; Membrane Transport Proteins - genetics; Membrane Transport Proteins - metabolism; Multigene Family; Operon; Promoter Regions, Genetic; Research Article; tigecycline; Tigecycline - pharmacology; tmexCD-toprJ; tmexCD-toprJ; evolution; antibiotic resistance; gene regulation; tigecycline
• ISSN: 2150-7511; 2150-7511
• DOI: 10.1128/mbio.00218-24

As antibiotic resistance seriously challenges global health, tigecycline is one of the few effective drugs in the pipeline against infections caused by multidrug-resistant pathogens. Our previous work identified a novel tigecycline resistance efflux pump gene cluster tmexCD1-toprJ1 in animals and humans, together with its various variants, a rising clinical concern. Herein, this study focused on how the local regulation modes of tmexCD1-toprJ1 evolved to a highly expressed efflux pump. Through comparative analysis between three tnfxB-tmexCD-toprJ homologs and their progenitor nfxB-mexCD-oprJ , modes, we demonstrated the evolutionary dynamics from a chromosomal silent gene to an active state. We found the de-repression of the local regulator and an increase of the promoter activity work together to promote a high production of drug efflux machines and enhance multidrug resistance. Our findings revealed that TMexCD1-TOprJ1 adopts a distinct evolutionary path to achieve higher multidrug resistance, urgently needing tight surveillance.