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

IF 4.7 3区医学 Q1 INFECTIOUS DISEASES

Journal of Infection and Public Health Pub Date : 2025-03-18 DOI:10.1016/j.jiph.2025.102761

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

{"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","authors":"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","doi":"10.1016/j.jiph.2025.102761","DOIUrl":null,"url":null,"abstract":"<div><h3>Background</h3><div>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 <em>Escherichia coli</em> isolates from the United Arab Emirates. We aimed to correlate their antibacterial efficacy with the genomic characteristics of the strains.</div></div><div><h3>Methods</h3><div>This study investigated 73 <em>E. coli</em> 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.</div></div><div><h3>Results</h3><div>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 <em>in vitro</em> 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).</div></div><div><h3>Conclusions</h3><div>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.</div></div>","PeriodicalId":16087,"journal":{"name":"Journal of Infection and Public Health","volume":"18 6","pages":"Article 102761"},"PeriodicalIF":4.7000,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Infection and Public Health","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S1876034125001108","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"INFECTIOUS DISEASES","Score":null,"Total":0}

引用次数: 0

Abstract

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.

查看原文本刊更多论文

求助全文

约1分钟内获得全文求助全文

来源期刊

Journal of Infection and Public Health PUBLIC, ENVIRONMENTAL & OCCUPATIONAL HEALTH -INFECTIOUS DISEASES

CiteScore

13.10

自引率

1.50%

发文量

203

审稿时长

96 days

期刊介绍： The Journal of Infection and Public Health, first official journal of the Saudi Arabian Ministry of National Guard Health Affairs, King Saud Bin Abdulaziz University for Health Sciences and the Saudi Association for Public Health, aims to be the foremost scientific, peer-reviewed journal encompassing infection prevention and control, microbiology, infectious diseases, public health and the application of healthcare epidemiology to the evaluation of health outcomes. The point of view of the journal is that infection and public health are closely intertwined and that advances in one area will have positive consequences on the other. The journal will be useful to all health professionals who are partners in the management of patients with communicable diseases, keeping them up to date. The journal is proud to have an international and diverse editorial board that will assist and facilitate the publication of articles that reflect a global view on infection control and public health, as well as emphasizing our focus on supporting the needs of public health practitioners. It is our aim to improve healthcare by reducing risk of infection and related adverse outcomes by critical review, selection, and dissemination of new and relevant information in the field of infection control, public health and infectious diseases in all healthcare settings and the community.