Leroux Pierre, Bornet Charleric, Bolla Jean-Michel, Cohen Anita
Aix Marseille Université, INSERM, SSA, MCT, 13385 Marseille, France.
Pharmacy Department, Hôpital Conception, Assistance Publique-Hôpitaux de Marseille, AP-HM, F-13005 Marseille, France.
Antibiotics (Basel). 2025 Jun 7;14(6):587. doi: 10.3390/antibiotics14060587.
Nowadays, antimicrobial resistance (AMR) is a growing global health threat, with carbapenem-resistant (CRE) posing particular concern due to limited treatment options. In fact, CRE have been classified as a critical priority by the World Health Organization (WHO). Carbapenem resistance results from complex mechanisms, often combining the production of hydrolytic enzymes such as β-lactamases with reduced membrane permeability and efflux system induction. The Ambler classification is an effective tool for differentiating the characteristics of serine-β-lactamases (SβLs) and metallo-β-lactamases (MβLs), including ESβLs (different from carbapenemases), KPC, NDM, VIM, IMP, AmpC (different from carbapenemases), and OXA-48. Recently approved inhibitor drugs, such as diazabicyclooctanones and boronic acid derivatives, only partially address this problem, not least because of their ineffectiveness against MβLs. However, compared with taniborbactam, xeruborbactam is the first bicyclic boronate in clinical development with a pan-β-lactamase inhibition spectrum, including the IMP subfamily. Recent studies explore strategies such as chemical optimization of β-lactamase inhibitor scaffolds, novel β-lactam/β-lactamase inhibitor combinations, and siderophore-antibiotic conjugates to enhance bacterial uptake. A deeper understanding of the mechanistic properties of the active sites enables rational drug design principles to be established for inhibitors targeting both SβLs and MβLs. This review aims to provide a comprehensive overview of current therapeutic strategies and future perspectives for the development of carbapenemase inhibitor drug candidates.
如今，抗菌药物耐药性（AMR）是一个日益严重的全球健康威胁，耐碳青霉烯类肠杆菌科细菌（CRE）因其治疗选择有限而备受关注。事实上，CRE已被世界卫生组织（WHO）列为关键优先事项。碳青霉烯耐药是由复杂机制导致的，通常是水解酶（如β-内酰胺酶）的产生与膜通透性降低和外排系统诱导相结合。安布勒分类法是区分丝氨酸-β-内酰胺酶（SβLs）和金属-β-内酰胺酶（MβLs）特性的有效工具，包括超广谱β-内酰胺酶（ESβLs，不同于碳青霉烯酶）、KPC、NDM、VIM、IMP、AmpC（不同于碳青霉烯酶）和OXA-48。最近获批的抑制剂药物，如二氮杂双环辛酮和硼酸衍生物，只能部分解决这个问题，尤其是因为它们对MβLs无效。然而，与替比巴坦相比，西瑞巴坦是首个处于临床开发阶段的具有泛β-内酰胺酶抑制谱（包括IMP亚家族）的双环硼酸盐。最近的研究探索了诸如β-内酰胺酶抑制剂支架的化学优化、新型β-内酰胺/β-内酰胺酶抑制剂组合以及铁载体-抗生素缀合物等策略，以增强细菌摄取。对活性位点机制特性的更深入理解有助于为同时靶向SβLs和MβLs的抑制剂建立合理的药物设计原则。本综述旨在全面概述碳青霉烯酶抑制剂候选药物的当前治疗策略和未来发展前景。
