Mutation- based mechanism and evolution of the potent multidrug efflux pump RE- CmeABC in Campylobacter

• 成果类型: Article
• 署名作者: Dai, Lei; Wu, Zuowei; Sahin, Orhan; Zhao, Shaohua; Yu, Edward W.; Zhang, Qijing
• 署名单位: Iowa State University; Iowa State University; US Food & Drug Administration (FDA); University System of Ohio; Case Western Reserve University
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-9257
• DOI: 10.1073/pnas.2415823121
• 发表日期: 2024-12-09
• 关键词: antibiotic-resistance; jejuni; sequence; SYSTEM; genome; alignment; mutagenesis; population; expression; bacteria

摘要

The resistance- nodulation-cell division (RND) superfamily of multidrug efflux systems are important players in mediating antibiotic resistance in gram- negative pathogens. Campylobacter jejuni, a major enteric pathogen, utilizes an RND-type transporter system, CmeABC, as the primary mechanism for extrusion of various antibiotics. Recently, a functionally potent variant of CmeABC (named RE- CmeABC) emerged in clinical Campylobacter isolates, conferring enhanced resistance to multiple antibiotic classes. Despite the clinical importance of RE- CmeABC, the molecular mechanisms for its functional gain and its evolutionary trajectory remain unknown. Here, we demonstrated that amino acid substitutions in RE-CmeB (inner membrane transporter), but not in RE-CmeA (periplasmic protein) and RE-CmeC (outer membrane protein), in conjunction with a nucleotide mutation in the promoter region of the efflux operon, are responsible for the functional gain of the multidrug efflux system. We also showed that RE- cmeABCis emerging globally and distributed in genetically diverse C. jejuni strains, suggesting its possible spread by horizontal gene transfer. Notably, many of RE- cmeABC harboring isolates were associated with the human host including strains from large disease outbreaks, indicating the clinical relevance and significance of RE- CmeABC. Evolutionary analysis indicated that RE-cmeB likely originated from Campylobacter coli, but its expansion mainly occurred in C. jejuni, possibly driven by antibiotic selection pressure. Additionally, RE-cmeB, but not RE-cmeA and RE-cmeC, experienced a selective sweep and was progressing to be fixed during evolution. Together, these results identify a mutation- based mechanism for functional gain in RE- CmeABC and reveal the key role of RE-CmeB in facilitating Campylobacter adaptation to antibiotic selection.