Genomic approach to evaluate the intrinsic antibacterial activity of novel diazabicyclooctanes (zidebactam and nacubactam) against clinical Escherichia coli isolates from diverse clonal lineages in the United Arab Emirates

Background: The spiking rise in the prevalence of multidrug-resistant (MDR) pathogens necessitates discovering new antimicrobial agents. This study aims to investigate the intrinsic activity of two novel diazabicyclooctane (DBO) β-lactamase inhibitors, zidebactam and nacubactam, against diverse MDR Escherichia coli isolates from the United Arab Emirates. We aimed to correlate their antibacterial efficacy with the genomic characteristics of the strains. Methods: This study investigated 73 E. coli strains and tested them for susceptibility to different antibiotics, including DBOs. PCR screening for carbapenemase and major β-lactamase genes was done. The strains were then grouped according to phenotypic and genotypic profiles. Whole-genome sequencing was employed to characterize the genetic landscape and clonality of selected 32 strains. Additionally, time-kill studies were conducted to confirm the bactericidal activity of DBOs. Results: Zidebactam demonstrated superior efficacy compared to nacubactam, primarily due to its higher affinity for penicillin-binding protein 2 (PBP2). Notably, zidebactam alone exhibited the most potent in vitro activity, outperforming both traditional β-lactams and novel antibiotics like cefiderocol. DBOs maintained effectiveness against strains harboring various resistance determinants, including NDM-5, OXA-181, CTX-M-15, SHV-12, CMY, and DHA. Genomic analysis revealed multiple mutations in PBP1–3, with PBP2 mutations correlating with DBO susceptibility variations. Importantly, DBOs remained highly effective against isolates with PBP mutations, even those belonging to high-risk clonal lineages (ST167, ST410, ST131). Time-kill studies confirmed the bactericidal activity of DBOs, with only one strain showing reduced susceptibility (MIC: 4 µg/ml). Conclusions: This study provides compelling evidence for the potential of DBOs, particularly zidebactam, as novel antibacterial agents. Their unique characteristics and broad-spectrum activity position them as promising candidates for future antibiotic development. While the inclusion of DBO therapies in the antibiotic arsenal could significantly impact MDR pathogen treatment, realizing their full potential requires further research, clinical evaluation, and vigilant monitoring of resistance mechanisms through integrated genomic approaches.