Virtual screening and biological activity evaluation of novel efflux pump inhibitors targeting AdeB

Multidrug-resistant Acinetobacter baumannii is a serious threat pathogen rapidly spreading in clinics and causing a range of complicated human infections. The major contributor to A. baumannii antibiotic resistance is the overproduction of AdeIJK and AdeABC multidrug efflux pumps of the resistance-nodulationdivision (RND) superfamily of proteins. The dominant role of efflux in antibiotic resistance and the relatively high permeability of the A. baumannii outer membrane to amphiphilic compounds make this pathogen a promising target for the discovery of clinically relevant efflux pump inhibitors. In this study, we identified 4,6-diaminoquoniline analogs with inhibitory activities against A. baumannii AdeIJK efflux pump and followed up on these compounds with a focused synthetic program to improve the target specificity and to reduce cytotoxicity. We identified several candidates that potentiate antibacterial activities of antibiotics erythromycin, tetracycline, and novobiocin not only in the laboratory antibiotic susceptible strain A. baumannii ATCC17978 but also in multidrug-resistant clinical isolates AB5075 and AYE. The best analogs potentiated the activities of antibiotics in low micromolar concentrations, did not have antibacterial activities on their own, inhibited AdeIJK-mediated efflux of its fluorescent substrate ethidium ion, and had low cytotoxicity in A549 human lung epithelial cells.

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Promising New Targets for the Treatment of Infections Caused by Acinetobacter baumannii: A Review

Malheiros Borges,

Kipnis,

Junior Neves

et al. 2024

CDT

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: Acinetobacter baumannii is a globally disseminated Gram-negative bacterium that causes several types of serious nosocomial infections, the most worrisome being ventilator-associated pneumonia and bacteremia related to using venous catheters. Due to its great ability to form biofilms, combined with its survival for prolonged periods on abiotic surfaces and its potential to acquire and control the genes that determine antibiotic resistance, A. baumannii is at the top of the World Health Organization’s priority list of pathogens in urgent need of new therapies. In this sense, this review aimed to present and discuss new molecular targets present in A. baumannii with potential for promising treatment approaches. This review highlights crucial molecular targets, including cell division proteins, membrane synthesis enzymes, and biofilm-associated components, offering promising targets for novel antimicrobial drug development against A. baumannii infections.

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Virtual screening and biological activity evaluation of novel efflux pump inhibitors targeting AdeB

Cited by 3 publications

References 62 publications

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Prognostic Model Construction of Disulfidptosis-Related Genes and Targeted Anticancer Drug Research in Pancreatic Cancer

AdeIJK Pump-Specific Inhibitors Effective against Multidrug Resistant Acinetobacter baumannii

Promising New Targets for the Treatment of Infections Caused by Acinetobacter baumannii: A Review

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