ArticlePloS one2017
Bifurcation kinetics of drug uptake by Gram-negative bacteria.
Article in PloS one, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 50 papers.
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Who cites it
50 citing papers in PubMed, 79 citations in OpenAlex.
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- Broad-Spectrum Naphthyl-Substituted Diaminoquinolines Inhibiting the AdeG Efflux Pump ofACS infectious diseases · 2026Article
- Substrate Specificity Checkpoints of the Multidrug Efflux Pump MexF fromACS infectious diseases · 2026Article
- Efflux pumps control intracellular drug-target kinetics by limiting rebinding in bacteria.Science advances · 2026Article
- Molecular basis for multidrug efflux by an anaerobic-associated RND transporter.Nature communications · 2025Article
- Metabolic control of porin permeability influences antibiotic resistance in Escherichia coli.Nature microbiology · 2025Article
- No two are alike: on the role ofAntimicrobial agents and chemotherapy · 2025Article
- Mutations in the proximal binding site and F-loop of AdeJ confer resistance to efflux pump inhibitors.Antimicrobial agents and chemotherapy · 2025Article
- Article
- Advances in methods and concepts provide new insight into antibiotic fluxes across the bacterial membrane.Communications biology · 2024Article
- MgbioRxiv : the preprint server for biology · 2024Article
- Predicting permeation of compounds across the outer membrane of P. aeruginosa using molecular descriptors.Communications chemistry · 2024Article
- Guiding the Way: Traditional Medicinal Chemistry Inspiration for Rational Gram-Negative Drug Design.Journal of medicinal chemistry · 2024Review
- The Art of War withAntibiotics (Basel, Switzerland) · 2023Review
- Conformational restriction shapes the inhibition of a multidrug efflux adaptor protein.Nature communications · 2023Article
- Dissociation kinetics of small-molecule inhibitors in Escherichia coli is coupled to physiological state of cells.Communications biology · 2023Article
- Functional Diversity of Gram-Negative Permeability Barriers Reflected in Antibacterial Activities and Intracellular Accumulation of Antibiotics.Antimicrobial agents and chemotherapy · 2023Article
- New understanding of multidrug efflux and permeation in antibiotic resistance, persistence, and heteroresistance.Annals of the New York Academy of Sciences · 2023Review
- Analysis of Orthogonal Efflux and Permeation Properties of Compounds Leads to the Discovery of New Efflux Pump Inhibitors.ACS infectious diseases · 2022Article
- Hacking the Permeability Barrier of Gram-Negative Bacteria.ACS central science · 2022Article
Corrections and comments
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Authors and funding
6 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Cell envelopes of many bacteria consist of two membranes studded with efflux transporters. Such organization protects bacteria from the environment and gives rise to multidrug resistance. We report a kinetic model that accurately describes the permeation properties of this system. The model predicts complex non-linear patterns of drug uptake complete with a bifurcation, which recapitulate the known experimental anomalies. We introduce two kinetic parameters, the efflux and barrier constants, which replace those of Michaelis and Menten for trans-envelope transport. Both compound permeation and efflux display transitions, which delineate regimes of efficient and inefficient efflux. The first transition is related to saturation of the transporter by the compound and the second one behaves as a bifurcation and involves saturation of the outer membrane barrier. The bifurcation was experimentally observed in live bacteria. We further found that active efflux of a drug can be orders of magnitude faster than its diffusion into a cell and that the efficacy of a drug depends both on its transport properties and therapeutic potency. This analysis reveals novel physical principles in the behavior of the cellular envelope, creates a framework for quantification of small molecule permeation into bacteria, and should invigorate structure-activity studies of novel antibiotics.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.