Dataset Information

In silico analyses of isoniazid and streptomycin resistance-associated mutations in Mycobacterium tuberculosis.

ABSTRACT: Multi-drug resistant tuberculosis is categorised by the World Health Organisation (WHO) as a public health crisis. In silico techniques were used to probe the structural basis of Mycobacterium tuberculosis resistance to isoniazid and streptomycin. Isoniazid resistance-associated mutations in InhA were predicted to reduce the binding affinity of NADH to InhA, without affecting INH-NAD (competitive-inhibitor) binding. Perturbation of the mutated residues was predicted (with the AlloSigMA server) to modulate the free energy of allosteric modulation of key binding site residues F41, F149, Y158 and W222. These results suggest that allosteric modulation of the protein structure may be key to the mechanism by which isoniazid resistance-associated mutations act. Mutations in the methyltransferase glucose-inhibited division gene B (GidB) are associated with streptomycin resistance. Molecular docking was carried out to predict the structure of the GidB bound to its substrate (s-adenosyl methionine). The effects of streptomycin resistance-associated mutations in GidB on protein stability and substrate binding were predicted (using SDM and mCSM-lig). All GidB mutants were predicted to disfavour SAM binding.

SUBMITTER: Dasoondi RS

PROVIDER: S-EPMC10006719 | biostudies-literature | 2023

REPOSITORIES: biostudies-literature

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In silico analyses of isoniazid and streptomycin resistance-associated mutations in Mycobacterium tuberculosis.

Dasoondi Rushikesh Singh RS Blundell Tom L TL Pandurangan Arun Prasad AP

Computational and structural biotechnology journal 20230221

Multi-drug resistant tuberculosis is categorised by the World Health Organisation (WHO) as a public health crisis. In silico techniques were used to probe the structural basis of Mycobacterium tuberculosis resistance to isoniazid and streptomycin. Isoniazid resistance-associated mutations in InhA were predicted to reduce the binding affinity of NADH to InhA, without affecting INH-NAD (competitive-inhibitor) binding. Perturbation of the mutated residues was predicted (with the AlloS ...[more]

PMID: 36915381

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Project description:BackgroundTuberculosis (TB) incidence and mortality are declining worldwide; however, poor detection of drug-resistant disease threatens to reverse current progress toward global TB control. Multiple, rapid molecular diagnostic tests have recently been developed to detect genetic mutations in Mycobacterium tuberculosis (Mtb) genes known to confer first-line drug resistance. Their utility, though, depends on the frequency and distribution of the resistance associated mutations in the pathogen population. Mutations associated with rifampicin resistance, one of the two first-line drugs, are well understood and appear to occur in a single gene region in >95% of phenotypically resistant isolates. Mutations associated with isoniazid, the other first-line drug, are more complex and occur in multiple Mtb genes.Objectives/methodologyA systematic review of all published studies from January 2000 through August 2013 was conducted to quantify the frequency of the most common mutations associated with isoniazid resistance, to describe the frequency at which these mutations co-occur, and to identify the regional differences in the distribution of these mutations. Mutation data from 118 publications were extracted and analyzed for 11,411 Mtb isolates from 49 countries.Principal findings/conclusionsGlobally, 64% of all observed phenotypic isoniazid resistance was associated with the katG315 mutation. The second most frequently observed mutation, inhA-15, was reported among 19% of phenotypically resistant isolates. These two mutations, katG315 and inhA-15, combined with ten of the most commonly occurring mutations in the inhA promoter and the ahpC-oxyR intergenic region explain 84% of global phenotypic isoniazid resistance. Regional variation in the frequency of individual mutations may limit the sensitivity of molecular diagnostic tests. Well-designed systematic surveys and whole genome sequencing are needed to identify mutation frequencies in geographic regions where rapid molecular tests are currently being deployed, providing a context for interpretation of test results and the opportunity for improving the next generation of diagnostics.

Project description:BackgroundThe acquisition of isoniazid (INH) resistance is alarming, considering its importance as a key drug that forms the core of multidrug treatment regimens for tuberculosis (TB). Genetic mutations in the katG and inhA promoter regions play crucial roles in INH resistance, but their prevalence varies geographically. This study aimed to identify the most common mutations in the katG and inhA genes in INH-resistant (INH-R) Mycobacterium tuberculosis (MTB) clinical isolates in Cameroon. The research also explored the relationships between these mutations and patients' demographics (age, sex, and sample type).MethodsWe conducted a retrospective cross-sectional laboratory-based study on 500 INH-R isolates (with or without resistance to other first-line drugs) at the National Tuberculosis Reference Laboratory (NTRL) in Cameroon between January 2014 and December 2020. GenoType MTBDRplus assay was performed on the retrieved isolates and the frequency of katG and inhA mutations were calculated. Chi-square tests were utilized to assess the associations between these mutations and patients' age, sex and sample type.ResultsA total of 410 (85.8%) culture-positive MTB isolates were analyzed, with a male-to-female ratio of 228 (55.6%) to 182 (44.4%) and an average age of 36.3 ± 13.4 years. Mutations in the katG and inhA genes were detected in 354 (86.3%) of cases, while 56 (13.7%) showed no mutations. Among the INH-R isolates, mutations in katG, inhA, and dual katG and inhA genes were present in 247 (60.2%), 76 (18.5%), and 31 (7.6%) isolates, respectively. Our analysis revealed significant associations between mutation prevalence and patient characteristics.ConclusionThis study reaffirmed the importance of the katG S315T substitution as a key indicator of INH resistance, with the inhA C-15T mutation providing additional support. However, a notable proportion of isoniazid-resistant isolates did not exhibit these mutations, underscoring the need to comprehend resistance mechanisms. Given that these mechanisms are strongly associated with varying levels of INH resistance, it is crucial that TB management strategies incorporate genetic profiling alongside patient demographics to optimize treatment outcomes and enhance control measures.

Dataset Information

In silico analyses of isoniazid and streptomycin resistance-associated mutations in Mycobacterium tuberculosis.

Publications

<i>In silico</i> analyses of isoniazid and streptomycin resistance-associated mutations in <i>Mycobacterium tuberculosis</i>.

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