近日，四川大学生命科学学院、动物疫病防控与绿色发展四川省重点实验室唐艺芝副教授等在ASM期刊mBio发表题为“The synergistic action of reduced membrane permeability and antibiotic sequestration as a novel mechanism for carbapenem resistance in Campylobacter”的研究论文。研究解析了弯曲菌新型碳青霉烯耐药机制，具有重要的科学价值与公共卫生意义。

Carbapenems are last-resort antibiotics against gram-negative pathogens, including multidrug-resistant Campylobacter. However, carbapenem-resistant Campylobacter strains are emerging and have been isolated in patients treated with carbapenems. This emerging resistance mechanism may be underpinned by multiple genetic determinants, yet it has not been systematically characterized or elucidated until now. In this study, two candidate mutations identified via resistance evolution and whole-genome sequencing were validated through genetic and functional assays. De novo structural modeling and molecular dynamics simulations elucidated the impact of mutations on protein dynamics. Furthermore, carbapenem hydrolysis and binding-pocket interactions were characterized using ultra-high-performance liquid chromatography, MM/PBSA calculations, and alanine substitution experiments. Our findings reveal that carbapenem resistance in Campylobacter is mediated by synergistic mutations in porA, encoding the major outer membrane protein (MOMP), and blaOXA-61, encoding a non-carbapenemase β-lactamase OXA-61. Specifically, the D157H substitution in MOMP induces structural and functional remodeling, thereby hindering meropenem translocation across the outer membrane, while a G → T transversion in the blaOXA-61 promoter leads to overexpression of the enzyme that sequesters meropenem instead of hydrolyzing it. Notably, either porA alteration or blaOXA-61 overexpression alone confers only a modest increase in carbapenem resistance (2- to 8-fold), whereas their synergy yields a high-level resistance (16- to 128-fold). Together, these results define a novel carbapenem resistance mechanism mediated by reduced porin permeability coupled with antibiotic sequestration acted by a non-carbapenemase β-lactamase. This synergistic mechanism explains clinical carbapenem resistance phenotypes in Campylobacter, facilitates diagnosis and surveillance, and likely represents a general carbapenem resistance strategy across other bacterial species.

（来源：mBio）