Functionally distinct mutations within AcrB underpin antibiotic resistance in different lifestyles

Trampari, Eleftheria, Prischi, Filippo, Vargiu, Attilio V., Abi-Assaf, Justin ORCID:, Bavro, Vassiliy N. and Webber, Mark A. (2023) Functionally distinct mutations within AcrB underpin antibiotic resistance in different lifestyles. npj Antimicrobials and Resistance, 1. ISSN 2731-8745

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Antibiotic resistance is a pressing healthcare challenge and is mediated by various mechanisms, including the active export of drugs via multidrug efflux systems, which prevent drug accumulation within the cell. Here, we studied how Salmonella evolved resistance to two key antibiotics, cefotaxime and azithromycin, when grown planktonically or as a biofilm. Resistance to both drugs emerged in both conditions and was associated with different substitutions within the efflux-associated transporter, AcrB. Azithromycin exposure selected for an R717L substitution, while cefotaxime for Q176K. Additional mutations in ramR or envZ accumulated concurrently with the R717L or Q176K substitutions respectively, resulting in clinical resistance to the selective antibiotics and cross-resistance to other drugs. Structural, genetic, and phenotypic analysis showed the two AcrB substitutions confer their benefits in profoundly different ways. R717L reduces steric barriers associated with transit through the substrate channel 2 of AcrB. Q176K increases binding energy for cefotaxime, improving recognition in the distal binding pocket, resulting in increased efflux efficiency. Finally, we show the R717 substitution is present in isolates recovered around the world.

Item Type: Article
Additional Information: Funding information: E.T. and M.A.W. were supported by the BBSRC Institute Strategic Programme Microbes in the Food Chain BB/R012504/1 and its constituent project BBS/E/F/000PR10349. Bioinformatics analyses were performed on CLIMB-computing servers, an infrastructure supported by a grant from the UK Medical Research Council (MR/L015080/1).
Faculty \ School: Faculty of Science > School of Biological Sciences
Faculty of Medicine and Health Sciences > Norwich Medical School
Depositing User: LivePure Connector
Date Deposited: 28 Feb 2023 17:31
Last Modified: 12 May 2023 10:31
DOI: 10.1038/s44259-023-00001-8


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