ChemInform Abstract: Microbial Fermentation‐Derived Inhibitors of Efflux‐Pump‐Mediated Drug Resistance

Lee, May D.; Galazzo, Jorge L.; Staley, Andrew L.; Lee, Julie C.; Warren, Mark S.; Fuernkranz, Hans A.; Chamberland, Suzanne; Lomovskaya, Olga; Miller, George H.

doi:10.1002/chin.200128235

Cited by 1 publication

(2 citation statements)

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“…For instance, two compounds (EA-371α and EA-371δ) were identified through screening of a library of 78 000 microbial fermentation extracts produced by multiple strains of Streptomyces spp. 166 These showed potent inhibition of the P. aeruginosa MexAB-OprM efflux system, but not of other RND efflux systems, such as MexCD-OprJ or MexEF-OprN. However, EA-371α was cytotoxic and considered unsuitable as a lead compound.…”

Section: Acsmentioning

confidence: 99%

“…However, EA-371α was cytotoxic and considered unsuitable as a lead compound. 166 Another Streptomyces extract library screen identified ethyl 4bromopyrrole-2-carboxylate (RP1) as an E. coli and P. aeruginosa efflux inhibitor. 167 In strains that overproduced AcrB, RP1 potentiated the activity of levofloxacin and tetracycline such that MICs were reduced to susceptible levels, although a more recent study could not demonstrate a significant reduction in the MIC values of levofloxacin or minocycline in E. coli.…”

Section: Acsmentioning

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: Acsmentioning

confidence: 99%

Section: Acsmentioning

confidence: 99%