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Computational protein design repurposed to explore enzyme vitality and help predict antibiotic resistance.
Front Mol Biosci
January 2023
Laboratoire de Biologie Structurale de la Cellule (CNRS UMR7654), Ecole Polytechnique, Palaiseau, France.
In response to antibiotics that inhibit a bacterial enzyme, resistance mutations inevitably arise. Predicting them ahead of time would aid target selection and drug design. The simplest resistance mechanism would be to reduce antibiotic binding without sacrificing too much substrate binding.
View Article and Find Full Text PDFStructural and functional analysis of the promiscuous AcrB and AdeB efflux pumps suggests different drug binding mechanisms.
Nat Commun
November 2021
Institute of Biochemistry, Goethe-University Frankfurt, Max-von-Laue-Straße 9, 60438, Frankfurt am Main, Germany.
Upon antibiotic stress Gram-negative pathogens deploy resistance-nodulation-cell division-type tripartite efflux pumps. These include a H/drug antiporter module that recognizes structurally diverse substances, including antibiotics. Here, we show the 3.
View Article and Find Full Text PDFPerturbed structural dynamics underlie inhibition and altered efflux of the multidrug resistance pump AcrB.
Nat Commun
November 2020
Department of Chemistry, King's College London, Britannia House, 7 Trinity Street, London, SE1 1DB, UK.
Article Synopsis
- Resistance-nodulation-division efflux pumps, like AcrB, are crucial for bacteria's ability to resist multiple drugs by expelling antimicrobial agents.
- Researchers used hydrogen/deuterium exchange mass spectrometry and molecular dynamics to study AcrB's structural dynamics in the presence of drugs.
- Findings indicate that inhibitors improve antibiotic effectiveness by changing the dynamics of the drug-binding pocket, and a specific alteration in the binding pocket from a resistant strain affects the pump's substrate export capability.
A study on the structure, mechanism, and biochemistry of kanamycin B dioxygenase (KanJ)-an enzyme with a broad range of substrates.
FEBS J
February 2021
Jerzy Haber Institute of Catalysis and Surface Chemistry, Polish Academy of Sciences, Krakow, Poland.
Kanamycin A is an aminoglycoside antibiotic isolated from Streptomyces kanamyceticus and used against a wide spectrum of bacteria, including Mycobacterium tuberculosis. Biosynthesis of kanamycin involves an oxidative deamination step catalyzed by kanamycin B dioxygenase (KanJ), thereby the C2' position of kanamycin B is transformed into a keto group upon release of ammonia. Here, we present for the first time, structural models of KanJ with several ligands, which along with the results of ITC binding assays and HPLC activity tests explain substrate specificity of the enzyme.
View Article and Find Full Text PDFPlasticity of Aminoglycoside Binding to Antibiotic Kinase APH(2″)-Ia.
Antimicrob Agents Chemother
July 2018
Department of Biochemistry, McGill University, Montreal, Canada
The APH(2″)-Ia aminoglycoside resistance enzyme forms the C-terminal domain of the bifunctional AAC(6')-Ie/APH(2″)-Ia enzyme and confers high-level resistance to natural 4,6-disubstituted aminoglycosides. In addition, reports have suggested that the enzyme can phosphorylate 4,5-disubstituted compounds and aminoglycosides with substitutions at the N1 position. Previously determined structures of the enzyme with bound aminoglycosides have not indicated how these noncanonical substrates may bind and be modified by the enzyme.
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