Understanding Rifampicin Resistance in Tuberculosis through a Computational Approach
The disease tuberculosis, caused by Mycobacterium tuberculosis (MTB), remains a major cause of morbidity and mortality in developing countries. The evolution of drug-resistant tuberculosis causes a foremost threat to global health. Most drug-resistant MTB clinical strains are showing resistance to i...
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BioMed Central
2014-12-01
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| Series: | Genomics & Informatics |
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| Online Access: | http://genominfo.org/upload/pdf/gni-12-276.pdf |
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| author | Satish Kumar Lingaraja Jena |
| author_facet | Satish Kumar Lingaraja Jena |
| author_sort | Satish Kumar |
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| description | The disease tuberculosis, caused by Mycobacterium tuberculosis (MTB), remains a major cause of morbidity and mortality in developing countries. The evolution of drug-resistant tuberculosis causes a foremost threat to global health. Most drug-resistant MTB clinical strains are showing resistance to isoniazid and rifampicin (RIF), the frontline anti-tuberculosis drugs. Mutation in rpoB, the beta subunit of DNA-directed RNA polymerase of MTB, is reported to be a major cause of RIF resistance. Amongst mutations in the well-defined 81-base-pair central region of the rpoB gene, mutation at codon 450 (S450L) and 445 (H445Y) is mainly associated with RIF resistance. In this study, we modeled two resistant mutants of rpoB (S450L and H445Y) using Modeller9v10 and performed a docking analysis with RIF using AutoDock4.2 and compared the docking results of these mutants with the wild-type rpoB. The docking results revealed that RIF more effectively inhibited the wild-type rpoB with low binding energy than rpoB mutants. The rpoB mutants interacted with RIF with positive binding energy, revealing the incapableness of RIF inhibition and thus showing resistance. Subsequently, this was verified by molecular dynamics simulations. This in silico evidence may help us understand RIF resistance in rpoB mutant strains. |
| format | Article |
| id | doaj-art-a661c47bb48048ed96724db927d909e1 |
| institution | Kabale University |
| issn | 1598-866X 2234-0742 |
| language | English |
| publishDate | 2014-12-01 |
| publisher | BioMed Central |
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| series | Genomics & Informatics |
| spelling | doaj-art-a661c47bb48048ed96724db927d909e12025-02-02T17:22:10ZengBioMed CentralGenomics & Informatics1598-866X2234-07422014-12-0112427628210.5808/GI.2014.12.4.276120Understanding Rifampicin Resistance in Tuberculosis through a Computational ApproachSatish Kumar0Lingaraja Jena1Bioinformatics Centre and Biochemistry, Mahatma Gandhi Institute of Medical Sciences, Sevagram 442 102, India.Bioinformatics Centre and Biochemistry, Mahatma Gandhi Institute of Medical Sciences, Sevagram 442 102, India.The disease tuberculosis, caused by Mycobacterium tuberculosis (MTB), remains a major cause of morbidity and mortality in developing countries. The evolution of drug-resistant tuberculosis causes a foremost threat to global health. Most drug-resistant MTB clinical strains are showing resistance to isoniazid and rifampicin (RIF), the frontline anti-tuberculosis drugs. Mutation in rpoB, the beta subunit of DNA-directed RNA polymerase of MTB, is reported to be a major cause of RIF resistance. Amongst mutations in the well-defined 81-base-pair central region of the rpoB gene, mutation at codon 450 (S450L) and 445 (H445Y) is mainly associated with RIF resistance. In this study, we modeled two resistant mutants of rpoB (S450L and H445Y) using Modeller9v10 and performed a docking analysis with RIF using AutoDock4.2 and compared the docking results of these mutants with the wild-type rpoB. The docking results revealed that RIF more effectively inhibited the wild-type rpoB with low binding energy than rpoB mutants. The rpoB mutants interacted with RIF with positive binding energy, revealing the incapableness of RIF inhibition and thus showing resistance. Subsequently, this was verified by molecular dynamics simulations. This in silico evidence may help us understand RIF resistance in rpoB mutant strains.http://genominfo.org/upload/pdf/gni-12-276.pdfdocking analysesdrug resistancemutationrifampicinrpoB |
| spellingShingle | Satish Kumar Lingaraja Jena Understanding Rifampicin Resistance in Tuberculosis through a Computational Approach Genomics & Informatics docking analyses drug resistance mutation rifampicin rpoB |
| title | Understanding Rifampicin Resistance in Tuberculosis through a Computational Approach |
| title_full | Understanding Rifampicin Resistance in Tuberculosis through a Computational Approach |
| title_fullStr | Understanding Rifampicin Resistance in Tuberculosis through a Computational Approach |
| title_full_unstemmed | Understanding Rifampicin Resistance in Tuberculosis through a Computational Approach |
| title_short | Understanding Rifampicin Resistance in Tuberculosis through a Computational Approach |
| title_sort | understanding rifampicin resistance in tuberculosis through a computational approach |
| topic | docking analyses drug resistance mutation rifampicin rpoB |
| url | http://genominfo.org/upload/pdf/gni-12-276.pdf |
| work_keys_str_mv | AT satishkumar understandingrifampicinresistanceintuberculosisthroughacomputationalapproach AT lingarajajena understandingrifampicinresistanceintuberculosisthroughacomputationalapproach |