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Home >> Publications >> Effect of mutation and genetic background on drug resistance in Mycobacterium tuberculosis.

Publication

Author(s):

Fenner L, Egger M, Bodmer T, Altpeter E, Zwahlen M, Jaton K, Pfyffer GE, Borrell S, Dubuis O, Bruderer T, Siegrist HH, Furrer H, Calmy A, Fehr J, Stalder JM, Ninet B, Bê_ttger EC, Gagneux S; Swiss HIV Cohort Study and the Swiss Molecular Epidemiology of Tuberculosis Study Group.

Pub Title:

Effect of mutation and genetic background on drug resistance in Mycobacterium tuberculosis.

Pub Date:

Jun 30 2012

Pub Region(s):

Southern Africa

Journal Issue:

6

Page Number:
3047-53

Journal:

Title: 
Antimicrobial Agents and Chemotherapy
Link: 
http://aac.asm.org/content/56/6/3047.long

PubMed: 22470121
Pub PDF: PDF icon 22470121.pdf

Abstract
Bacterial factors may contribute to the global emergence and spread of drug-resistant tuberculosis (TB). Only a few studies have reported on the interactions between different bacterial factors. We studied drug-resistant Mycobacterium tuberculosis isolates from a nationwide study conducted from 2000 to 2008 in Switzerland. We determined quantitative drug resistance levels of first-line drugs by using Bactec MGIT-960 and drug resistance genotypes by sequencing the hot-spot regions of the relevant genes. We determined recent transmission by molecular methods and collected clinical data. Overall, we analyzed 158 isolates that were resistant to isoniazid, rifampin, or ethambutol, 48 (30.4%) of which were multidrug resistant. Among 154 isoniazid-resistant strains, katG mutations were associated with high-level and inhA promoter mutations with low-level drug resistance. Only katG(S315T) (65.6% of all isoniazid-resistant strains) and inhA promoter -15C/T (22.7%) were found in molecular clusters. M. tuberculosis lineage 2 (includes Beijing genotype) was associated with any drug resistance (adjusted odds ratio [OR], 3.0; 95% confidence interval [CI], 1.7 to 5.6; P < 0.0001). Lineage 1 was associated with inhA promoter -15C/T mutations (OR, 6.4; 95% CI, 2.0 to 20.7; P = 0.002). We found that the genetic strain background influences the level of isoniazid resistance conveyed by particular mutations (interaction tests of drug resistance mutations across all lineages; P < 0.0001). In conclusion, M. tuberculosis drug resistance mutations were associated with various levels of drug resistance and transmission, and M. tuberculosis lineages were associated with particular drug resistance-conferring mutations and phenotypic drug resistance. Our study also supports a role for epistatic interactions between different drug resistance mutations and strain genetic backgrounds in M. tuberculosis drug resistance.

PMID: 22470121 [PubMed - indexed for MEDLINE]

PMCID: PMC3370767

 
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Citation:

Fenner L, Egger M, Bodmer T, Altpeter E, Zwahlen M, Jaton K, Pfyffer GE, Borrell S, Dubuis O, Bruderer T, Siegrist HH, Furrer H, Calmy A, Fehr J, Stalder JM, Ninet B, Böttger EC, Gagneux S; Swiss HIV Cohort Study and the Swiss Molecular Epidemiology of Tuberculosis Study Group. Effect of mutation and genetic background on drug resistance in Mycobacterium tuberculosis. Antimicrob Agents Chemother. 2012 Jun;56(6):3047-53. doi: 10.1128/AAC.06460-11. Epub 2012 Apr 2. PubMed PMID: 22470121; PubMed Central PMCID: PMC3370767.