title: inhA promoter mutations: a gateway to extensively drug-resistant tuberculosis in South Africa?
abstract: METHODS
  Western Cape and Eastern Cape Provinces, South Africa.
  
  
  OBJECTIVE
  To assess the potential association between the evolution of extensively drug-resistant (XDR) strains of Mycobacterium tuberculosis and mutations in the inhA promoter or the katG gene.
  
  
  METHODS
  Analysis of the frequency distribution of isoniazid (INH) resistance conferring mutations in a population sample of drug-resistant isolates of M. tuberculosis.
  
  
  RESULTS
  In the Western Cape and Eastern Cape Provinces, the percentage of isolates exhibiting inhA promoter mutations increased significantly from respectively 48.4% and 62.4% in multidrug-resistant tuberculosis (MDR-TB) isolates to 85.5% and 91.9% in XDR isolates. Data from the Western Cape revealed that significantly more XDR-TB isolates showed mutations in the inhA promoter than in katG (85.5% vs. 60.9%, P < 0.01), while the respective proportions were equal for INH-resistant non-MDR-TB isolates (∼30%).
  
  
  CONCLUSIONS
  inhA promoter mutations are strongly associated with XDR-TB in South Africa. We suggest that this is due to the dual resistance to ethionamide and (low-dose) INH conferred by inhA promoter mutations. The use of molecular probe assays such as the GenoType® MTBDRplus assay, which allows the detection of inhA promoter mutations, could enable treatment regimens to be adjusted depending on the pharmacogenetic properties of the mutations detected.
authors.affiliation: Department of Science and Technology/National Research Foundation Centre of Excellence for Biomedical Tuberculosis Research/Medical Research Council Centre for Molecular and Cellular Biology, Division of Molecular Biology and Human Genetics, Faculty of Health Sciences, Stellenbosch University, Cape Town, South Africa. bmuller@sun.ac.za
authors.forename: B
authors.initials: B
authors.lastname: Müller
authors.forename: E M
authors.initials: EM
authors.lastname: Streicher
authors.forename: K G P
authors.initials: KG
authors.lastname: Hoek
authors.forename: M
authors.initials: M
authors.lastname: Tait
authors.forename: A
authors.initials: A
authors.lastname: Trollip
authors.forename: M E
authors.initials: ME
authors.lastname: Bosman
authors.forename: G J
authors.initials: GJ
authors.lastname: Coetzee
authors.forename: E M
authors.initials: EM
authors.lastname: Chabula-Nxiweni
authors.forename: E
authors.initials: E
authors.lastname: Hoosain
authors.forename: N C
authors.initials: NC
authors.lastname: Gey van Pittius
authors.forename: T C
authors.initials: TC
authors.lastname: Victor
authors.forename: P D
authors.initials: PD
authors.lastname: van Helden
authors.forename: R M
authors.initials: RM
authors.lastname: Warren
mesh_terms: D000995:Antitubercular Agents / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000235:genetics*; D054908:Extensively Drug-Resistant Tuberculosis / Q000188:drug therapy* / Q000453:epidemiology / Q000235:genetics; D005838:Genotype; D006801:Humans; D015336:Molecular Probe Techniques; D009154:Mutation; D009169:Mycobacterium tuberculosis / Q000187:drug effects / Q000302:isolation & purification; D010088:Oxidoreductases / Q000235:genetics*; D010597:Pharmacogenetics; D011401:Promoter Regions, Genetic; D013019:South Africa / Q000453:epidemiology
chemical_list: D000995:Antitubercular Agents; D001426:Bacterial Proteins; D010088:Oxidoreductases; C085257:InhA protein, Mycobacterium