Combined Structure- and Ligand-Based Approach for the Identification of Inhibitors of AcrAB-TolC in <i>Escherichia coli</i>

Pisoni, Lily A.; Semple, Susan J.; Liu, Sida; Sykes, Matthew J.; Venter, Henrietta

doi:10.1021/acsinfecdis.3c00350

Cited by 2 publications

(3 citation statements)

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“…189 Recently, a combined structure-and ligand-based model developed at the University of South Australia was used to predict inhibitors of AcrB in E. coli. 190 Ivacaftor, used for the treatment of cystic fibrosis, was identified through screening a library of 1391 FDA-approved drugs using this model, and efflux inhibition activity and in vitro potentiation activity of erythromycin and chloramphenicol in E. coli was demonstrated. 190…”

Section: Acs Infectiousmentioning

confidence: 99%

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Extending the Potency and Lifespan of Antibiotics: Inhibitors of Gram-Negative Bacterial Efflux Pumps

Duffey,

Jumde,

da Costa

et al. 2024

ACS Infect. Dis.

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Efflux is a natural process found in all prokaryotic and eukaryotic cells that removes a diverse range of substrates from inside to outside. Many antibiotics are substrates of bacterial efflux pumps, and modifications to the structure or overexpression of efflux pumps are an important resistance mechanism utilized by many multidrug-resistant bacteria. Therefore, chemical inhibition of bacterial efflux to revitalize existing antibiotics has been considered a promising approach for antimicrobial chemotherapy over two decades, and various strategies have been employed. In this review, we provide an overview of bacterial multidrug resistance (MDR) efflux pumps, of which the resistance nodulation division (RND) efflux pumps are considered the most clinically relevant in Gram-negative bacteria, and describe over 50 efflux inhibitors that target such systems. Although numerous efflux inhibitors have been identified to date, none have progressed into clinical use because of formulation, toxicity, and pharmacokinetic issues or a narrow spectrum of inhibition. For these reasons, the development of efflux inhibitors has been considered a difficult and complex area of research, and few active preclinical studies on efflux inhibitors are in progress. However, recently developed tools, including but not limited to computational tools including molecular docking models, offer hope that further research on efflux inhibitors can be a platform for research and development of new bacterial efflux inhibitors.

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Section: Acs Infectiousmentioning

confidence: 99%

“… 190 Ivacaftor, used for the treatment of cystic fibrosis, was identified through screening a library of 1391 FDA-approved drugs using this model, and efflux inhibition activity and in vitro potentiation activity of erythromycin and chloramphenicol in E. coli was demonstrated. 190 …”

Section: Identification Of Efflux Inhibitorsmentioning

confidence: 99%

Extending the Potency and Lifespan of Antibiotics: Inhibitors of Gram-Negative Bacterial Efflux Pumps

Duffey,

Jumde,

da Costa

et al. 2024

ACS Infect. Dis.

View full text Add to dashboard Cite

show abstract

“…Drug efflux pumps are proteins that expel many different classes of antibiotics from bacterial cells thereby conferring multidrug resistance to these bacteria hence efflux pump inhibitors have the potential to restore the activity of multiple classes of antibiotics. 38 Despite the obvious advantages of efflux pump inhibitors and efforts by many research groups including ours, 39 efflux pump inhibitors are yet to progress to clinical trials.…”

Section: Looking Forwardmentioning

confidence: 99%