The Structural Basis of <i>Mycobacterium tuberculosis</i> RpoB Drug-Resistant Clinical Mutations on Rifampicin Drug Binding
Tuberculosis (TB), caused by the <i>Mycobacterium tuberculosis</i> infection, continues to be a leading cause of morbidity and mortality in developing countries. Resistance to the first-line anti-TB drugs, isoniazid (INH) and rifampicin (RIF), is a major drawback to effective TB treatmen...
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| Format: | Article |
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MDPI AG
2022-01-01
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| Series: | Molecules |
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| Online Access: | https://www.mdpi.com/1420-3049/27/3/885 |
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| author | Arnold Amusengeri Asifullah Khan Özlem Tastan Bishop |
| author_facet | Arnold Amusengeri Asifullah Khan Özlem Tastan Bishop |
| author_sort | Arnold Amusengeri |
| collection | DOAJ |
| description | Tuberculosis (TB), caused by the <i>Mycobacterium tuberculosis</i> infection, continues to be a leading cause of morbidity and mortality in developing countries. Resistance to the first-line anti-TB drugs, isoniazid (INH) and rifampicin (RIF), is a major drawback to effective TB treatment. Genetic mutations in the β-subunit of the DNA-directed RNA polymerase (<i>rpoB</i>) are reported to be a major reason of RIF resistance. However, the structural basis and mechanisms of these resistant mutations are insufficiently understood. In the present study, thirty drug-resistant mutants of <i>rpoB</i> were initially modeled and screened against RIF via a comparative molecular docking analysis with the wild-type (WT) model. These analyses prioritized six mutants (Asp441Val, Ser456Trp, Ser456Gln, Arg454Gln, His451Gly, and His451Pro) that showed adverse binding affinities, molecular interactions, and RIF binding hinderance properties, with respect to the WT. These mutant models were subsequently analyzed by molecular dynamics (MD) simulations. One-hundred nanosecond all-atom MD simulations, binding free energy calculations, and a dynamic residue network analysis (DRN) were employed to exhaustively assess the impact of mutations on RIF binding dynamics. Considering the global structural motions and protein–ligand binding affinities, the Asp441Val, Ser456Gln, and His454Pro mutations generally yielded detrimental effects on RIF binding. Locally, we found that the electrostatic contributions to binding, particularly by Arg454 and Glu487, might be adjusted to counteract resistance. The DRN analysis revealed that all mutations mostly distorted the communication values of the critical hubs and may, therefore, confer conformational changes in rpoB to perturb RIF binding. In principle, the approach combined fundamental molecular modeling tools for robust “global” and “local” level analyses of structural dynamics, making it well suited for investigating other similar drug resistance cases. |
| first_indexed | 2024-03-09T23:28:48Z |
| format | Article |
| id | doaj.art-f523026e525e4432b373de5e62f34b6c |
| institution | Directory Open Access Journal |
| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-03-09T23:28:48Z |
| publishDate | 2022-01-01 |
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| record_format | Article |
| series | Molecules |
| spelling | doaj.art-f523026e525e4432b373de5e62f34b6c2023-11-23T17:14:06ZengMDPI AGMolecules1420-30492022-01-0127388510.3390/molecules27030885The Structural Basis of <i>Mycobacterium tuberculosis</i> RpoB Drug-Resistant Clinical Mutations on Rifampicin Drug BindingArnold Amusengeri0Asifullah Khan1Özlem Tastan Bishop2Research Unit in Bioinformatics (RUBi), Department of Biochemistry and Microbiology, Rhodes University, Grahamstown 6140, South AfricaDepartment of Biochemistry, Abdul Wali Khan University Mardan (AWKUM), Mardan 23200, PakistanResearch Unit in Bioinformatics (RUBi), Department of Biochemistry and Microbiology, Rhodes University, Grahamstown 6140, South AfricaTuberculosis (TB), caused by the <i>Mycobacterium tuberculosis</i> infection, continues to be a leading cause of morbidity and mortality in developing countries. Resistance to the first-line anti-TB drugs, isoniazid (INH) and rifampicin (RIF), is a major drawback to effective TB treatment. Genetic mutations in the β-subunit of the DNA-directed RNA polymerase (<i>rpoB</i>) are reported to be a major reason of RIF resistance. However, the structural basis and mechanisms of these resistant mutations are insufficiently understood. In the present study, thirty drug-resistant mutants of <i>rpoB</i> were initially modeled and screened against RIF via a comparative molecular docking analysis with the wild-type (WT) model. These analyses prioritized six mutants (Asp441Val, Ser456Trp, Ser456Gln, Arg454Gln, His451Gly, and His451Pro) that showed adverse binding affinities, molecular interactions, and RIF binding hinderance properties, with respect to the WT. These mutant models were subsequently analyzed by molecular dynamics (MD) simulations. One-hundred nanosecond all-atom MD simulations, binding free energy calculations, and a dynamic residue network analysis (DRN) were employed to exhaustively assess the impact of mutations on RIF binding dynamics. Considering the global structural motions and protein–ligand binding affinities, the Asp441Val, Ser456Gln, and His454Pro mutations generally yielded detrimental effects on RIF binding. Locally, we found that the electrostatic contributions to binding, particularly by Arg454 and Glu487, might be adjusted to counteract resistance. The DRN analysis revealed that all mutations mostly distorted the communication values of the critical hubs and may, therefore, confer conformational changes in rpoB to perturb RIF binding. In principle, the approach combined fundamental molecular modeling tools for robust “global” and “local” level analyses of structural dynamics, making it well suited for investigating other similar drug resistance cases.https://www.mdpi.com/1420-3049/27/3/885drug resistancemutationsrifampicin<i>rpoB</i>molecular dynamics simulationsdynamic residue network analysis |
| spellingShingle | Arnold Amusengeri Asifullah Khan Özlem Tastan Bishop The Structural Basis of <i>Mycobacterium tuberculosis</i> RpoB Drug-Resistant Clinical Mutations on Rifampicin Drug Binding Molecules drug resistance mutations rifampicin <i>rpoB</i> molecular dynamics simulations dynamic residue network analysis |
| title | The Structural Basis of <i>Mycobacterium tuberculosis</i> RpoB Drug-Resistant Clinical Mutations on Rifampicin Drug Binding |
| title_full | The Structural Basis of <i>Mycobacterium tuberculosis</i> RpoB Drug-Resistant Clinical Mutations on Rifampicin Drug Binding |
| title_fullStr | The Structural Basis of <i>Mycobacterium tuberculosis</i> RpoB Drug-Resistant Clinical Mutations on Rifampicin Drug Binding |
| title_full_unstemmed | The Structural Basis of <i>Mycobacterium tuberculosis</i> RpoB Drug-Resistant Clinical Mutations on Rifampicin Drug Binding |
| title_short | The Structural Basis of <i>Mycobacterium tuberculosis</i> RpoB Drug-Resistant Clinical Mutations on Rifampicin Drug Binding |
| title_sort | structural basis of i mycobacterium tuberculosis i rpob drug resistant clinical mutations on rifampicin drug binding |
| topic | drug resistance mutations rifampicin <i>rpoB</i> molecular dynamics simulations dynamic residue network analysis |
| url | https://www.mdpi.com/1420-3049/27/3/885 |
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