ArticleProceedings of the National Academy of Sciences of the United States of America2015
AcrB drug-binding pocket substitution confers clinically relevant resistance and altered substrate specificity.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 98 papers.
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Who cites it
98 citing papers in PubMed.
- Carbapenem-ResistantAntibiotics (Basel, Switzerland) · 2026Review
- Molecular mechanisms of disinfectant resistance inJAC-antimicrobial resistance · 2026Article
- Article
- Cloning and Characterizing Multidrug Efflux Pumps.Methods in molecular biology (Clifton, N.J.) · 2026Article
- Computer Simulations of Multidrug Efflux Pumps of the Resistance-Nodulation-Cell Division Superfamily.Methods in molecular biology (Clifton, N.J.) · 2026Article
- Structural and functional analysis of theProceedings of the National Academy of Sciences of the United States of America · 2025Article
- Drug delivery dynamics dictate evolution of bacterial antibiotic responses.The ISME journal · 2025Article
- Mutation-based mechanism and evolution of the potent multidrug efflux pump RE-CmeABC inProceedings of the National Academy of Sciences of the United States of America · 2024Article
- Structural and functional diversity of Resistance-Nodulation-Division (RND) efflux pump transporters with implications for antimicrobial resistance.Microbiology and molecular biology reviews : MMBR · 2024Review
- Dynamics of drug delivery determines course of evolution of antibiotic responses in bacteria.bioRxiv : the preprint server for biology · 2024Article
- Structural analysis of resistance-nodulation cell division transporters.Microbiology and molecular biology reviews : MMBR · 2024Review
- Antimicrobial Resistance in Livestock: A Serious Threat to Public Health.Antibiotics (Basel, Switzerland) · 2024Review
- Article
- Extending the Potency and Lifespan of Antibiotics: Inhibitors of Gram-Negative Bacterial Efflux Pumps.ACS infectious diseases · 2024Review
- Molecular insights into the determinants of substrate specificity and efflux inhibition of the RND efflux pumps AcrB and AdeB.Microbiology (Reading, England) · 2024Review
- Hound: a novel tool for automated mapping of genotype to phenotype in bacterial genomes assembled de novo.Briefings in bioinformatics · 2024Article
- Pyridylpiperazine efflux pump inhibitor boosts in vivo antibiotic efficacy against K. pneumoniae.EMBO molecular medicine · 2024Article
- Antimicrobial, antiproliferative activities and molecular docking of metabolites from Alternaria alternata.AMB Express · 2023Article
- AcrAB-TolC, a major efflux pump in Gram negative bacteria: toward understanding its operation mechanism.BMB reports · 2023Review
- Comparative genomics uncovered differences between clinical and environmental populations ofMicrobial genomics · 2023Article
38 more citing papers are in PubMed but not listed here.
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Authors and funding
13 authors.
Funding
Abstract
The incidence of multidrug-resistant bacterial infections is increasing globally and the need to understand the underlying mechanisms is paramount to discover new therapeutics. The efflux pumps of Gram-negative bacteria have a broad substrate range and transport antibiotics out of the bacterium, conferring intrinsic multidrug resistance (MDR). The genomes of pre- and posttherapy MDR clinical isolates of Salmonella Typhimurium from a patient that failed antibacterial therapy and died were sequenced. In the posttherapy isolate we identified a novel G288D substitution in AcrB, the resistance-nodulation division transporter in the AcrAB-TolC tripartite MDR efflux pump system. Computational structural analysis suggested that G288D in AcrB heavily affects the structure, dynamics, and hydration properties of the distal binding pocket altering specificity for antibacterial drugs. Consistent with this hypothesis, recreation of the mutation in standard Escherichia coli and Salmonella strains showed that G288D AcrB altered substrate specificity, conferring decreased susceptibility to the fluoroquinolone antibiotic ciprofloxacin by increased efflux. At the same time, the substitution increased susceptibility to other drugs by decreased efflux. Information about drug transport is vital for the discovery of new antibacterials; the finding that one amino acid change can cause resistance to some drugs, while conferring increased susceptibility to others, could provide a basis for new drug development and treatment strategies.
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