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J Comput Aided Mol Des. 2019 Oct;33(10):927-940. doi: 10.1007/s10822-019-00229-5. Epub 2019 Oct 26.

A computational study of the molecular basis of antibiotic resistance in a DXR mutant.

Author information

1
Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Institut National de La Santé et de La Recherche Médicale (INSERM), U1258 / Centre National de Recherche Scientifique (CNRS), UMR7104 / Université de Strasbourg, 1 rue Laurent Fries, P. Box 10142, 67404, Illkirch, CEDEX, France.
2
INSA, INRA, CNRS, TBI, Université de Toulouse, 135 avenue de Rangueil, 31400, Toulouse, France.
3
Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Institut National de La Santé et de La Recherche Médicale (INSERM), U1258 / Centre National de Recherche Scientifique (CNRS), UMR7104 / Université de Strasbourg, 1 rue Laurent Fries, P. Box 10142, 67404, Illkirch, CEDEX, France. rstote@igbmc.fr.

Abstract

Proteins of the independent mevalonate pathway for isoprenoid biosynthesis are important targets for the development of new antibacterial compounds as this pathway is present in most pathogenic organisms such as Mycobacterium tuberculosis, DPlasmodium falciparum and Escherichia coli, but is not present in mammalian species, including humans. Deoxy-D-xylulose 5-phosphate reductoisomerase (DXR) is an important target in this pathway and the most effective DXR inhibitor to date is fosmidomycin, which is used to treat malaria and, more recently, tuberculosis. Recently, Armstrong C. M. et al. showed that a mutant of DXR, S222T, induces a loss of the fosmidomycin inhibition efficiency, even though the bacteria culture is still viable and able to produce isoprenoids. As this represents a potential fosmidomycin-resistant mutation, it is important to understand the mechanism of this apparent mutation-induced resistance to fosmidomycin. Here, we used molecular dynamics simulations and Molecular Mechanics/Poisson Boltzmann Surface Area analysis to understand the structural and energetic basis of the resistance. Our results suggest that the point mutation results in changes to the structural dynamics of an active site loop that probably protects the active site and facilitates enzymatic reaction. From the simulation analysis, we also showed that the mutation results in changes in the interaction energy profiles in a way that can explain the observed activity of the mutant protein toward the natural inhibitor deoxy-D-xylulose 5-phosphate. These results should be taken into consideration in future efforts to develop new therapeutic antibiotic compounds that target DXR.

KEYWORDS:

DXR; Drug design; Free energy binding; MEP; MM/PBSA; Molecular dynamics simulations; Mutation

PMID:
31654265
DOI:
10.1007/s10822-019-00229-5

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