ArticleChemical science2017
Predicting allosteric mutants that increase activity of a major antibiotic resistance enzyme.
Article in Chemical science, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers.
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Who cites it
17 citing papers in PubMed.
- Structural comparison of substrate-binding pockets of serine β-lactamases in classes A, C, and D.Journal of enzyme inhibition and medicinal chemistry · 2025Review
- Resistance to Allosteric Inhibitors.Journal of molecular biology · 2025Review
- Friends and relatives: insight into conformational regulation from orthologues and evolutionary lineages using KIF and KIN.Faraday discussions · 2024Article
- Dissecting Allosteric Mutations for Antibiotic Resistance by Time-Dependent Linear Response Theory.Journal of chemical theory and computation · 2024Article
- Unveiling the structural features that regulate carbapenem deacylation in KPC-2 through QM/MM and interpretable machine learning.Physical chemistry chemical physics : PCCP · 2023Article
- Effect of ultrasonic treatment on the activity of sugar metabolism relative enzymes and quality of coconut water.Ultrasonics sonochemistry · 2021Article
- Can We Exploit β-Lactamases Intrinsic Dynamics for Designing More Effective Inhibitors?Antibiotics (Basel, Switzerland) · 2020Review
- Discovery of cryptic allosteric sites using reversed allosteric communication by a combined computational and experimental strategy.Chemical science · 2020Article
- Harnessing Conformational Plasticity to Generate Designer Enzymes.Journal of the American Chemical Society · 2020Review
- Structure-Based Analysis of Cryptic-Site Opening.Structure (London, England : 1993) · 2020Article
- Article
- Adaptive ensemble simulations of biomolecules.Current opinion in structural biology · 2018Review
- Predicting allostery and microbial drug resistance with molecular simulations.Current opinion in structural biology · 2018Review
- Conformational dynamics and enzyme evolution.Journal of the Royal Society, Interface · 2018Review
- Directed Evolution Mimics Allosteric Activation by Stepwise Tuning of the Conformational Ensemble.Journal of the American Chemical Society · 2018Article
- An overview of recent molecular dynamics applications as medicinal chemistry tools for the undruggable site challenge.MedChemComm · 2018Review
- Conformational Intermediate That Controls KPC-2 Catalysis and Beta-Lactam Drug Resistance.ACS catalysis · 2018Article
Corrections and comments
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Authors and funding
5 authors.
Funding
Abstract
The CTX-M family of beta lactamases mediate broad-spectrum antibiotic resistance and are present in the majority of drug-resistant Gram-negative bacterial infections worldwide. Allosteric mutations that increase catalytic rates of these drug resistance enzymes have been identified in clinical isolates but are challenging to predict prospectively. We have used molecular dynamics simulations to predict allosteric mutants increasing CTX-M9 drug resistance, experimentally testing top mutants using multiple antibiotics. Purified enzymes show an increase in catalytic rate and efficiency, while mutant crystal structures show no detectable changes from wild-type CTX-M9. We hypothesize that increased drug resistance results from changes in the conformational ensemble of an acyl intermediate in hydrolysis. Machine-learning analyses on the three top mutants identify changes to the binding-pocket conformational ensemble by which these allosteric mutations transmit their effect. These findings show how molecular simulation can predict how allosteric mutations alter active-site conformational equilibria to increase catalytic rates and thus resistance against common clinically used antibiotics.
Identifiers
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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.