Advancements in the fight against globally distributed OXA-48 carbapenemase: evaluating the new generation of carbapenemase inhibitors

Abstract

[Abstract] 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 in vitro, 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.info:eu-repo/grantAgreement/ISCIII/Programa Estatal de Generación de Conocimiento y Fortalecimiento del Sistema Español de I+D+I/PI20%2F01212/ES/DESARROLLO Y EVALUACION DE NUEVAS MOLECULAS ANTIMICROBIANAS DIRIGIDAS A PATOGENOS MULTIRRESISTENTES (INHIBIDORES DE ß-LACTAMASAS Y CONJUGADOS TETRACICLINAS-SIDEROFOROS). ESTUDIO NACIONAL ACINETOBACTER SPP.info:eu-repo/grantAgreement/ISCIII/Programa Estatal para impulsar la investigación científico-técnica y su transferencia/PI23%2F00851/ES/Actividad in vivo de nuevos inhibidores de carbapenemasas frente a patógenos críticos multirresistentes: K. pneumoniae productor de carbapenemasas y P. aeruginosa.info:eu-repo/grantAgreement/ISCIII/Programa Estatal de Generación de Conocimiento y Fortalecimiento del Sistema Español de I+D+I/PI21%2F00704/ES/VACUNAS AUXOTROFAS ORALES PARA LA ERRADICACION DE BACTERIAS INTESTINALES: COLONIZACIÓN INTESTINAL POR KLEBSIELLA PNEUMONIAE MULTIRRESISTENTE COMO MODELOinfo:eu-repo/grantAgreement/ISCIII/Programa Estatal para Impulsar la Investigación Científico-Técnica y su Transferencia/PI22%2F01212/ES/Inhibidores de carbapenemasas: actividad frente a Enterobacterales productores de carbapenemasas, mecanismos e impacto en la evolución de la resistencia antimicrobiana (PROTECT)Instituto de Salud Carlos III; CB21/13/00055Xunta de Galicia; IN607A 2020/05Xunta de Galicia; IN607D 2024/008info:eu-repo/grantAgreement/AEI/Programa Estatal para Impulsar la Investigación Científico-Técnica y su Transferencia/PID2022-136963OB-I00/ES/NUEVOS AGENTES ANTIBACTERIANOS DE PRECISION Y TERAPIAS COMBINADAS PARA COMBATIR INFECCIONES MULTIRRESISTENTESXunta de Galicia; ED431C 2021/29Xunta de Galicia; ED431G 2023/03info:eu-repo/grantAgreement/ISCIII/Programa Estatal de Generación de Conocimiento y Fortalecimiento del Sistema Español de I+D+I/PI20%2F00686/ES/DETECCION RAPIDA DE RESISTENCIAS ANTIBIOTICAS MEDIANTE ESPECTROMETRIA DE MASAS MALDI-TOFInstituto de Salud Carlos III; CM23/00095Instituto de Salud Carlos III; CM23/00104Instituto de Salud Carlos III; JR23/00036This work was supported by Projects PI20/01212 and PI23/00851 awarded to A.B., Project PI21/00704 awarded to G.B., and Project PI22/01212 awarded to J.A.-S., funded by the Instituto de Salud Carlos III (ISCIII) and co-funded by the European Union. The work was also supported by CIBER-Consorcio Centro de Investigación Biomédica en Red- de Enfermedades Infecciosas, Instituto de Salud Carlos III (CB21/13/00055), Ministerio de Ciencia e Innovación and Unión Europea—NextGenerationEU and by project IN607A 2020/05 (GAIN-Agencia Gallega de InnovaciónConsellería de Economía, Emprego e Industria) awarded to G.B., project IN607D 2021/12 awarded to A.B and IN607D 2024/008 to J.A.-S. Financial support from the Spanish State Agency of Research (PID2022-136963OB-I00/AEI/10.13039/501100011033, CG-B), the Xunta de Galicia (ED431C 2021/29 and Centro singular de investigación de Galicia accreditation 2023–2027 [ED431G 2023/03], C.G.-B.], and the European Regional Development Fund (ERDF). T.B.-M. was financially supported by the ISCIII project PI20/00686 and by the Rio Hortega program (ISCIII, CM23/00095). S.R.-P. was financially supported by the ISCIII Río Hortega program (CM23/00104). I.A.-G. was financially supported by the Juan Rodés program (ISCIII, JR23/00036). L.G.-P. was financially supported by the ISCIII project PI21/00704 and by the PFIS program (ISCIII, FI23/00074). J.C.V.-U. was financially supported by the Xunta de Galicia (IN606B-2022/009). J.A.-S. was financially supported by the Juan Rodés program (ISCIII, JR21/00026). P.G.-S. was financially supported by IN606A 2021/021 Grant (Xunta de Galicia). M.O.-G. was financially supported by IN606A 2023/023 Grant (Xunta de Galicia)