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...
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Elsevier
2025-06-01
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| Series: | Journal of Infection and Public Health |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S1876034125001108 |
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| author | Farah Al-Marzooq Akela Ghazawi Maitha Alshamsi Abdulrahman Alzaabi Omar Aleissaee Hamad Almansoori Abdullah Alsaadi Rauda Aldhaheri Hafsa Ahli Lana Daoud Amna Ahmad Timothy Collyns Seema Oommen |
| author_facet | Farah Al-Marzooq Akela Ghazawi Maitha Alshamsi Abdulrahman Alzaabi Omar Aleissaee Hamad Almansoori Abdullah Alsaadi Rauda Aldhaheri Hafsa Ahli Lana Daoud Amna Ahmad Timothy Collyns Seema Oommen |
| author_sort | Farah Al-Marzooq |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-750a293e8f7940969a9b34ece9cfd6bc |
| institution | DOAJ |
| issn | 1876-0341 |
| language | English |
| publishDate | 2025-06-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Journal of Infection and Public Health |
| spelling | doaj-art-750a293e8f7940969a9b34ece9cfd6bc2025-08-20T02:50:55ZengElsevierJournal of Infection and Public Health1876-03412025-06-0118610276110.1016/j.jiph.2025.102761Genomic 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 EmiratesFarah Al-Marzooq0Akela Ghazawi1Maitha Alshamsi2Abdulrahman Alzaabi3Omar Aleissaee4Hamad Almansoori5Abdullah Alsaadi6Rauda Aldhaheri7Hafsa Ahli8Lana Daoud9Amna Ahmad10Timothy Collyns11Seema Oommen12Department of Medical Microbiology and Immunology, College of Medicine and Health Sciences, United Arab Emirates University, Al-Ain, United Arab Emirates; Correspondence to: Department of Medical Microbiology and Immunology, College of Medicine and Health Sciences, United Arab Emirates University, P.O. Box No. 15551, Al Ain, United Arab Emirates.Department of Medical Microbiology and Immunology, College of Medicine and Health Sciences, United Arab Emirates University, Al-Ain, United Arab EmiratesDepartment of Medical Microbiology and Immunology, College of Medicine and Health Sciences, United Arab Emirates University, Al-Ain, United Arab Emirates; Tawam Hospital, Al-Ain, United Arab EmiratesDepartment of Medical Microbiology and Immunology, College of Medicine and Health Sciences, United Arab Emirates University, Al-Ain, United Arab EmiratesDepartment of Medical Microbiology and Immunology, College of Medicine and Health Sciences, United Arab Emirates University, Al-Ain, United Arab EmiratesDepartment of Medical Microbiology and Immunology, College of Medicine and Health Sciences, United Arab Emirates University, Al-Ain, United Arab EmiratesDepartment of Medical Microbiology and Immunology, College of Medicine and Health Sciences, United Arab Emirates University, Al-Ain, United Arab EmiratesDepartment of Medical Microbiology and Immunology, College of Medicine and Health Sciences, United Arab Emirates University, Al-Ain, United Arab EmiratesDepartment of Medical Microbiology and Immunology, College of Medicine and Health Sciences, United Arab Emirates University, Al-Ain, United Arab EmiratesDepartment of Medical Microbiology and Immunology, College of Medicine and Health Sciences, United Arab Emirates University, Al-Ain, United Arab EmiratesDepartment of Medical Microbiology and Immunology, College of Medicine and Health Sciences, United Arab Emirates University, Al-Ain, United Arab EmiratesTawam Hospital, Al-Ain, United Arab EmiratesBurjeel Medical City/coLAB, Abu Dhabi, United Arab EmiratesBackground: 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.http://www.sciencedirect.com/science/article/pii/S1876034125001108DiazabicyclooctanesZidebactamNacubactamEscherichia coliWhole-genome sequencing |
| spellingShingle | Farah Al-Marzooq Akela Ghazawi Maitha Alshamsi Abdulrahman Alzaabi Omar Aleissaee Hamad Almansoori Abdullah Alsaadi Rauda Aldhaheri Hafsa Ahli Lana Daoud Amna Ahmad Timothy Collyns Seema Oommen 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 Journal of Infection and Public Health Diazabicyclooctanes Zidebactam Nacubactam Escherichia coli Whole-genome sequencing |
| title | 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 |
| title_full | 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 |
| title_fullStr | 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 |
| title_full_unstemmed | 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 |
| title_short | 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 |
| title_sort | 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 |
| topic | Diazabicyclooctanes Zidebactam Nacubactam Escherichia coli Whole-genome sequencing |
| url | http://www.sciencedirect.com/science/article/pii/S1876034125001108 |
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