《生命科学》 2026, 38(5): 905-916
细菌对碳青霉烯类抗生素的耐药机制与防治策略研究进展
摘 要：
碳青霉烯类抗生素是治疗多重耐药革兰氏阴性菌感染的关键药物，其耐药性的全球蔓延已成为临床抗感染领域面临的严峻问题。碳青霉烯耐药菌（CRO）的核心耐药机制包括：碳青霉烯酶水解、外膜孔蛋白缺失、外排泵过表达、生物膜形成以及细菌靶位改变，这些机制间存在显著的协同增效效应。耐药基因通过质粒、转座子进行水平转移，并凭借环境-临床传播链持续扩散，加剧了流行趋势。同时，本文也系统阐述了CRO的防治策略，包括新型β-内酰胺酶抑制剂、外排泵抑制剂靶向干预、噬菌体-CRISPR基因编辑技术及多药联用方案。未来需深度融合耐药进化机制研究与跨学科干预，为遏制碳青霉烯耐药提供解决方案。
通讯作者：付加芳 , Email:fujiafang@sdfmu.edu.cn
Abstract:
Carbapenem antibiotics are key drugs for treating life-threatening infections caused by multidrug-resistant Gramnegative bacteria, because of their broad antibacterial spectrum and stability against most β-lactamases. However, the increasingly serious carbapenem-resistant organisms (CROs) infections have become a major challenge in the field of antiinfection. This review summarizes the resistance mechanism of CRO, the dissemination of CRO, as well as the prevention and control strategies and current situation of CRO. The development of CRO resistance often results from the synergistic effects of multiple mechanisms. Key resistance mechanisms include: (1) production of carbapenemases that hydrolyze carbapenems, including serine β-lactamases (Ambler classes A and D, e.g., KPC, OXA-48) and metallo-β-lactamases (class B, e.g., NDM, VIM, IMP); (2) reduced drug permeability due to mutations or loss of outer membrane porins (e.g., OmpK35/OmpK36 in Enterobacteriaceae, OprD in P. aeruginosa), limiting antibiotic influx; (3) overexpression of multidrug efflux pumps (e.g., AcrAB-TolC, MexAB-OprM, AdeABC), which actively expel antibiotics; (4) enhanced biofilm formation, creating a physiophysical barrier that restricts antibiotic penetration and promotes a tolerant, slow-growing population; and (5) mutations or modifications at the target site, particularly mutations or modifications in penicillin-binding proteins (PBPs). These mechanisms rarely function independently but often work together, thereby enhancing drug resistance. For example, porin loss combined with weak hydrolysis by extended-spectrum β-lactamases (ESBLs) or AmpC enzymes can confer significant resistance to carbapenems such as ertapenem. The rapid dissemination of carbapenem resistance is propelled by two main drivers: efficient horizontal gene transfer (HGT) and the global spread of successful clones. Key resistance genes, notably blaKPC, blaNDM, and blaOXA-48-like, are frequently located on mobile genetic elements such as conjugative plasmids, transposons, and integrative and conjugative elements (ICEs), facilitating rapid dissemination across bacterial species and genera. Common environmental stressors in healthcare and community settings, including subinhibitory concentrations of antibiotics, disinfectants (such as chlorinated compounds), and heavy metals, can further promote HGT by triggering bacterial stress responses such as the SOS response. Clonal lineages characterized by strong environmental fitness/persistence, and high pathogenicity have become predominant on a global scale, such as Klebsiella pneumoniae sequence type (ST) 11 (and its sublineage ST11-KL64) in Asia, Acinetobacter baumannii international clone (IC) 2, and Pseudomonas aeruginosa ST235. These clones disseminate widely through healthcare networks, international travel, and environmental reservoirs, forming a persistent and mobile drug-resistant pool. Active screening is one of the core strategies for containing the intra-hospital transmission of CRO-resistant bacteria. Rapid molecular testing (e.g., PCR for carbapenemase genes), combined with stringent infection control measures (contact isolation, enhanced environmental cleaning), remains fundamental for containment of CRO. Currently, clinical treatment for CRO infections primarily relies on multidrug combination therapy, with the specific regimen determined by the pathogen′s drug resistance phenotype and the site of infection. The new treatment strategies currently under development include: (1) developing novel inhibitors targeting specific resistance mechanisms, such as MBL inhibitors and efflux pump blockers; (2) exploring “drug repurposing” strategies to identify β-lactamase inhibitory activity in existing non-antibiotic drugs (e.g., the antifungal agent tavaborole); (3) applying precision biocontrol agents like engineered bacteriophages and CRISPR-Cas systems to selectively lyse resistant bacteria or inactivate resistant genes; and (4) optimizing synergistic combination regimens, such as fosfomycin paired with a carbapenem or a novel β-lactamase inhibitor. In summary, the CRO crisis demands integrated strategies: developing resistance-breaking agents (e.g., dual-function molecules or combination strategies) to counter synergistic resistance mechanisms and implementing proactive One Health surveillance to track high-risk clones across clinical and environmental settings.
Communication Author：FU Jia-Fang , Email:fujiafang@sdfmu.edu.cn
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