Outeda-García Michelle, Arca-Suárez Jorge, Lence Emilio, Rodriguez-Coello Arianna, Maceiras Romina, Blanco-Martin Tania, Guijarro-Sánchez Paula, Gonzalez-Pinto Lucia, Alonso-Garcia Isaac, García-Pose Andrea, Muras Andrea, Rodriguez-Pallares Salud, Lasarte-Monterrubio Cristina, Gonzalez-Bello Concepción, Vázquez-Ucha Juan Carlos, Bou German, Beceiro Alejandro
Microbiology department, A Coruna University Hospital (CHUAC), Institute of Biomedical Research of A Coruna (INIBIC), A Coruna, Spain.
CIBER de Enfermedades Infecciosas (CIBERINFEC), A Coruna, Spain.
Antimicrob Agents Chemother. 2025 Feb 13;69(2):e0161424. doi: 10.1128/aac.01614-24. Epub 2025 Jan 10.
Carbapenemase OXA-48 and its variants pose a serious threat to the development of effective treatments for bacterial infections. OXA-48-producing Enterobacterales are the most prevalent carbapenemase-producing bacteria in large parts of the world. Although these bacteria exhibit low-level carbapenem resistance , the infections they cause are challenging to treat with conventional therapies, owing to their spread and complex detection in clinical settings. However, numerous β-lactamase inhibitors (BLIs) are currently in the pipeline or late clinical stages. To assess the potential of these compounds, this study compared the efficacy against OXA-48 of novel β-lactamase inhibitors, specifically the 1,6-diazabicyclo[3,2,1]octanes (DBOs) avibactam, relebactam, zidebactam, nacubactam, and durlobactam, along with the cyclic and bicyclic boronates vaborbactam, taniborbactam, and xeruborbactam. The extensive kinetics assays identified xeruborbactam, taniborbactam, and durlobactam, together with the already established avibactam, as BLIs with superior biochemical performance. Susceptibility testing further validated these findings but also demonstrated significantly improved bacterial killing by the DBOs zidebactam, nacubactam, and durlobactam. On the other hand, binding studies demonstrated the superior inhibitory capacity of the BLIs durlobactam and xeruborbactam. Combinations, such as cefepime/zidebactam, meropenem/nacubactam, and sulbactam/durlobactam, show promising activity against OXA-48-producing Enterobacterales, while ceftazidime/avibactam, cefepime/taniborbactam, and meropenem/xeruborbactam combinations also appear highly active, largely due to the excellent kinetics of these new inhibitors. Overall, this comprehensive analysis provides important insights into the effectiveness of new BLIs against OXA-48-producing Enterobacterales, highlighting xeruborbactam, durlobactam, and avibactam as leading candidates. Additionally, BLIs like zidebactam, nacubactam, and taniborbactam also showed potential in addressing the clinical challenges posed by OXA-48-mediated antimicrobial resistance.
碳青霉烯酶OXA - 48及其变体对细菌感染有效治疗方法的发展构成严重威胁。产OXA - 48的肠杆菌科细菌是世界大部分地区最普遍的产碳青霉烯酶细菌。尽管这些细菌表现出低水平的碳青霉烯耐药性，但由于它们在临床环境中的传播和复杂检测，用传统疗法治疗它们所引起的感染具有挑战性。然而，目前有许多β-内酰胺酶抑制剂（BLIs）正处于研发或临床后期阶段。为了评估这些化合物的潜力，本研究比较了新型β-内酰胺酶抑制剂对OXA - 48的疗效，特别是1,6 - 二氮杂双环[3,2,1]辛烷（DBOs）阿维巴坦、瑞来巴坦、齐德巴坦、那库巴坦和杜洛巴坦，以及环状和双环硼酸酯类药物瓦博巴坦、他尼硼巴坦和西鲁巴坦。广泛的动力学分析确定西鲁巴坦、他尼硼巴坦和杜洛巴坦以及已有的阿维巴坦为具有卓越生化性能的β-内酰胺酶抑制剂。药敏试验进一步验证了这些发现，同时也证明了齐德巴坦、那库巴坦和杜洛巴坦这几种DBOs显著提高了细菌杀灭效果。另一方面，结合研究表明杜洛巴坦和西鲁巴坦这两种β-内酰胺酶抑制剂具有卓越的抑制能力。联合用药，如头孢吡肟/齐德巴坦、美罗培南/那库巴坦和舒巴坦/杜洛巴坦，对产OXA - 48的肠杆菌科细菌显示出有前景的活性，而头孢他啶/阿维巴坦、头孢吡肟/他尼硼巴坦和美罗培南/西鲁巴坦联合用药也显得活性很高，这很大程度上归因于这些新型抑制剂出色的动力学性能。总体而言，这项全面分析为新型β-内酰胺酶抑制剂对产OXA - 48的肠杆菌科细菌的有效性提供了重要见解，突出了西鲁巴坦、杜洛巴坦和阿维巴坦作为主要候选药物。此外，齐德巴坦、那库巴坦和他尼硼巴坦等β-内酰胺酶抑制剂在应对OXA - 48介导的抗菌耐药性所带来的临床挑战方面也显示出潜力。
