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Isoniazid resistance levels of Mycobacterium tuberculosis can largely be predicted by high-confidence resistance-conferring mutations.

ABSTRACT: The majority of Mycobacterium tuberculosis isolates resistant to isoniazid harbour a mutation in katG. Since these mutations cause a wide range of minimum inhibitory concentrations (MICs), largely below the serum level reached with higher dosing (15?mg/L upon 15-20?mg/kg), the drug might still remain partly active in presence of a katG mutation. We therefore investigated which genetic mutations predict the level of phenotypic isoniazid resistance in clinical M. tuberculosis isolates. To this end, the association between known and unknown isoniazid resistance-conferring mutations in whole genome sequences, and the isoniazid MICs of 176 isolates was examined. We found mostly moderate-level resistance characterized by a mode of 6.4?mg/L for the very common katG Ser315Thr mutation, and always very high MICs (?19.2?mg/L) for the combination of katG Ser315Thr and inhA c-15t. Contrary to common belief, isolates harbouring inhA c-15t alone, partly also showed moderate-level resistance, particularly when combined with inhA Ser94Ala. No overt association between low-confidence or unknown mutations, except in katG, and isoniazid resistance (level) was found. Except for the rare katG deletion, line probe assay is thus not sufficiently accurate to predict the level of isoniazid resistance for a single mutation in katG or inhA.

SUBMITTER: Lempens P

PROVIDER: S-EPMC5818527 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature

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Isoniazid resistance levels of Mycobacterium tuberculosis can largely be predicted by high-confidence resistance-conferring mutations.

Lempens Pauline P Meehan Conor J CJ Vandelannoote Koen K Fissette Kristina K de Rijk Pim P Van Deun Armand A Rigouts Leen L de Jong Bouke C BC

Scientific reports 20180219 1

The majority of Mycobacterium tuberculosis isolates resistant to isoniazid harbour a mutation in katG. Since these mutations cause a wide range of minimum inhibitory concentrations (MICs), largely below the serum level reached with higher dosing (15 mg/L upon 15-20 mg/kg), the drug might still remain partly active in presence of a katG mutation. We therefore investigated which genetic mutations predict the level of phenotypic isoniazid resistance in clinical M. tuberculosis isolates. To this end ...[more]

PMID: 29459669

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Project description:BACKGROUND:Accurate diagnosis of tuberculosis, especially by using rapid molecular assays, can reduce transmission of drug resistant tuberculosis in communities. However, the frequency of resistance conferring mutations varies with geographic location of Mycobacterium tuberculosis, and this affects the efficiency of rapid molecular assays in detecting resistance. This has created need for characterizing drug resistant isolates from different settings to investigate frequencies of resistance conferring mutations. Here, we describe the prevalence and patterns of rifampicin- and isoniazid- resistance conferring mutations in isolates from Uganda, which could be useful in the management of MDR-TB patients in Uganda and other countries in sub-Saharan Africa. RESULTS:Ninety seven M. tuberculosis isolates were characterized, of which 38 were MDR, seven rifampicin-resistant, 12 isoniazid-mono-resistant, and 40 susceptible to rifampicin and isoniazid. Sequence analysis of the rpoB rifampicin-resistance determining region (rpoB/RRDR) revealed mutations in six codons: 588, 531, 526, 516, 513, and 511, of which Ser531Leu was the most frequent (40%, 18/45). Overall, the three mutations (Ser531Leu, His526Tyr, Asp516Tyr) frequently associated with rifampicin-resistance occurred in 76% of the rifampicin resistant isolates while 18% (8/45) of the rifampicin-resistant isolates lacked mutations in rpoB/RRDR. Furthermore, sequence analysis of katG and inhA gene promoter revealed mainly the Ser315Thr (76%, 38/50) and C(-15)T (8%, 4/50) mutations, respectively. These two mutations combined, which are frequently associated with isoniazid-resistance, occurred in 88% of the isoniazid resistant isolates. However, 20% (10/50) of the isoniazid-resistant isolates lacked mutations both in katG and inhA gene promoter. The sensitivity of sequence analysis of rpoB/RRDR for rifampicin-resistance via detection of high confidence mutations (Ser531Leu, His526Tyr, Asp516Tyr) was 81%, while it was 77% for analysis of katG and inhA gene promoter to detect isoniazid-resistance via detection of high confidence mutations (Ser315Thr, C(-15)T, T(-8)C). Furthermore, considering the circulating TB genotypes in Uganda, the isoniazid-resistance conferring mutations were more frequent in M. tuberculosis lineage 4/sub-lineage Uganda, perhaps explaining why this genotype is weakly associated with MDR-TB. CONCLUSION:Sequence analysis of rpoB/RRDR, katG and inhA gene promoter is useful in detecting rifampicin/isoniazid resistant M. tuberculosis isolates in Uganda however, about ≤20% of the resistant isolates lack known resistance-conferring mutations hence rapid molecular assays may not detect them as resistant.

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.

Dataset Information

Isoniazid resistance levels of Mycobacterium tuberculosis can largely be predicted by high-confidence resistance-conferring mutations.

Publications

Isoniazid resistance levels of Mycobacterium tuberculosis can largely be predicted by high-confidence resistance-conferring mutations.

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