ArticleProceedings of the National Academy of Sciences of the United States of America2016
Molecular basis for inhibition of AcrB multidrug efflux pump by novel and powerful pyranopyridine derivatives.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 104 papers.
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Who cites it
104 citing papers in PubMed.
- Molecular mechanism of transition-state inhibitors of bacterial antibiotic efflux pumps.npj antimicrobials and resistance · 2026Article
- NV716 acts as an envelope-active adjuvant that enhances antibiotic accumulation in Pseudomonas aeruginosa.npj antimicrobials and resistance · 2026Article
- Broad-Spectrum Naphthyl-Substituted Diaminoquinolines Inhibiting the AdeG Efflux Pump ofACS infectious diseases · 2026Article
- Efflux pumps control intracellular drug-target kinetics by limiting rebinding in bacteria.Science advances · 2026Article
- Computer Simulations of Multidrug Efflux Pumps of the Resistance-Nodulation-Cell Division Superfamily.Methods in molecular biology (Clifton, N.J.) · 2026Article
- Exploring allosteric efflux pump inhibitors and the role of bacterial membrane potential in modulating drug resistance.Frontiers in microbiology · 2026Review
- Targeting the AcrAB-TolC efflux pump by small molecules selectively addressing the outer membrane factor TolC.Frontiers in pharmacology · 2026Article
- RND efflux pump inhibitor-like natural products as antibiotic adjuvants against multidrug-resistant gram-negative bacteria: a graded-evidence review.Frontiers in microbiology · 2026Review
- Formulation, Development, and Optimization of Fast Dissolving Tablets Containing Tapentadol Hydrochloride.Pharmaceutical nanotechnology · 2026Article
- Conformational plasticity across phylogenetic clusters of RND multidrug efflux pumps and its impact on substrate specificity.Nature communications · 2025Article
- Mutations in the proximal binding site and F-loop of AdeJ confer resistance to efflux pump inhibitors.Antimicrobial agents and chemotherapy · 2025Article
- Efflux-Mediated Resistance inAntibiotics (Basel, Switzerland) · 2025Review
- Small-molecule strategies to combat antibiotic resistance: mechanisms, modifications, and contemporary approaches.RSC advances · 2025Review
- Antimicrobial and Anti-Efflux Machinery of FDA-Approved Proton Pump Inhibitors and Vitamins AgainstMicroorganisms · 2025Article
- Impact of exporter proteins and their engineering on the productivity of Corynebacterium.Applied microbiology and biotechnology · 2025Review
- Unveiling Antibiotic Resistance: Genome Sequencing of Streptomycin-ResistantMicroorganisms · 2024Article
- Rhodamine 19 Alkyl Esters as Effective Antibacterial Agents.International journal of molecular sciences · 2024Article
- Extending the Potency and Lifespan of Antibiotics: Inhibitors of Gram-Negative Bacterial Efflux Pumps.ACS infectious diseases · 2024Review
- Pyrrole-based inhibitors of RND-type efflux pumps reverse antibiotic resistance and display anti-virulence potential.PLoS pathogens · 2024Article
- Comparative reassessment of AcrB efflux inhibitors reveals differential impact of specific pump mutations on the activity of potent compounds.Microbiology spectrum · 2024Article
44 more citing papers are in PubMed but not listed here.
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12 authors.
Funding
Abstract
The Escherichia coli AcrAB-TolC efflux pump is the archetype of the resistance nodulation cell division (RND) exporters from Gram-negative bacteria. Overexpression of RND-type efflux pumps is a major factor in multidrug resistance (MDR), which makes these pumps important antibacterial drug discovery targets. We have recently developed novel pyranopyridine-based inhibitors of AcrB, which are orders of magnitude more powerful than the previously known inhibitors. However, further development of such inhibitors has been hindered by the lack of structural information for rational drug design. Although only the soluble, periplasmic part of AcrB binds and exports the ligands, the presence of the membrane-embedded domain in AcrB and its polyspecific binding behavior have made cocrystallization with drugs challenging. To overcome this obstacle, we have engineered and produced a soluble version of AcrB [AcrB periplasmic domain (AcrBper)], which is highly congruent in structure with the periplasmic part of the full-length protein, and is capable of binding substrates and potent inhibitors. Here, we describe the molecular basis for pyranopyridine-based inhibition of AcrB using a combination of cellular, X-ray crystallographic, and molecular dynamics (MD) simulations studies. The pyranopyridines bind within a phenylalanine-rich cage that branches from the deep binding pocket of AcrB, where they form extensive hydrophobic interactions. Moreover, the increasing potency of improved inhibitors correlates with the formation of a delicate protein- and water-mediated hydrogen bond network. These detailed insights provide a molecular platform for the development of novel combinational therapies using efflux pump inhibitors for combating multidrug resistant Gram-negative pathogens.
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