Article ; Online: A computational study of the molecular basis of antibiotic resistance in a DXR mutant.
Journal of computer-aided molecular design
2019 Volume 33, Issue 10, Page(s) 927–940
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 ... ...
| 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. |
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| MeSH term(s) | Aldose-Ketose Isomerases/antagonists & inhibitors ; Aldose-Ketose Isomerases/genetics ; Aldose-Ketose Isomerases/metabolism ; Anti-Bacterial Agents/administration & dosage ; Anti-Bacterial Agents/metabolism ; Binding Sites ; Drug Resistance, Microbial ; Escherichia coli/drug effects ; Escherichia coli/enzymology ; Fosfomycin/administration & dosage ; Fosfomycin/analogs & derivatives ; Fosfomycin/metabolism ; Ligands ; Models, Theoretical ; Molecular Dynamics Simulation ; Mutation ; Mycobacterium tuberculosis/drug effects ; Mycobacterium tuberculosis/enzymology ; Pentosephosphates/metabolism ; Protein Conformation |
| Chemical Substances | Anti-Bacterial Agents ; Ligands ; Pentosephosphates ; Fosfomycin (2N81MY12TE) ; fosmidomycin (5829E3D9I9) ; xylulose-5-phosphate (60802-29-1) ; 1-deoxy-D-xylulose 5-phosphate reductoisomerase (EC 1.1.1.267) ; Aldose-Ketose Isomerases (EC 5.3.1.-) |
| Language | English |
| Publishing date | 2019-10-26 |
| Publishing country | Netherlands |
| Document type | Journal Article ; Research Support, Non-U.S. Gov't |
| ZDB-ID | 808166-9 |
| ISSN | 1573-4951 ; 0920-654X |
| ISSN (online) | 1573-4951 |
| ISSN | 0920-654X |
| DOI | 10.1007/s10822-019-00229-5 |
| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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