Abstract
BackgroundEthambutol (EMB) is a first-line drug for the treatment of tuberculosis (TB). Resistance to EMB in Mycobacterium tuberculosis isolates is mediated by mutations in several genes involved in arabinan synthesis notably three emb (arabinosyl transferase) and iniA (isoniazid-inducible) genes. Most epidemiologically unrelated EMB-resistant M. tuberculosis strains contain mutations at embB codons 306, 406 and 497, embC-embA intergenic region (IGR) and iniA codon 501 (iniA501).ObjectiveTo develop a more comprehensive molecular screen for EMB-resistance detectioamong epidemiologically unrelated EMB-resistant M. tuberculosis strains previously analyzed for embB codon 306, 406 and 497 mutations by including analysis of mutations at iniA501 and in embC-embA IGR.MethodsFifty consecutive and phenotypically documented EMB-resistant and 25 pansusceptible M. tuberculosis strains isolated from 75 different TB patients over a four-year period in Kuwait were analyzed. Mutations at iniA501 were detected by PCR amplification followed by restriction fragment length polymorphism (RFLP) patterns generated with Hpy 99 I. Direct DNA sequencing was used to confirm RFLP results and for detecting mutations in embC-embA IGR.ResultsNearly same number of EMB-resistant M. tuberculosis strains were resistant to EMB alone and EMB together with additional resistance to rifampicin and isoniazid (9 of 50, 18% and 11 of 50, 22%, respectively). All the 25 pansusceptible strains contained wild-type sequences at iniA501 and in embC-embA IGR. The analysis of 50 EMB-resistant M. tuberculosis isolates showed that only one strain contained a mutated iniA501 while no mutation was detected in embC-embA IGR in any of the isolate.ConclusionAnalysis of iniA501 and embC-embA IGR in epidemiologically unrelated EMB-resistant M. tuberculosis isolates in Kuwait indicate that mutations at these locations occur very infrequently and their inclusion for the development of a comprehensive molecular screen will make only minor contribution towards rapid EMB resistance detection.
Highlights
Ethambutol (EMB) is a first-line drug for the treatment of tuberculosis (TB)
The analysis of 50 EMB-resistant M. tuberculosis isolates showed that only one strain contained a mutated iniA codon 501 (iniA501) while no mutation was detected in embC-embA intergenic region (IGR) in any of the isolate
Analysis of iniA501 and embC-embA IGR in epidemiologically unrelated EMB-resistant M. tuberculosis isolates in Kuwait indicate that mutations at these locations occur very infrequently and their inclusion for the development of a comprehensive molecular screen will make only minor contribution towards rapid EMB resistance detection
Summary
Ethambutol (EMB) is a first-line drug for the treatment of tuberculosis (TB). Co-infection with human immunodeficiency virus (HIV) and increasing incidence of infections with drug-resistant strains of Mycobacterium tuberculosis are steadily worsening the problem of TB [3,4]. Infections with drug-resistant, multidrug-resistant (MDR) (resistant to at least rifampicin and isoniazid) strains of M. tuberculosis (MDR-TB) are associated with higher mortality [4,5]. Molecular methods for rapidly identifying drug-resistant strains of M. tuberculosis are urgently needed to avoid inadequate treatment since phenotypic drug susceptibility testing by radiometric method requires 4–14 days after the primary culture has been isolated [6]. A simple and rapid line probe assay has been developed recently for detection of resistance of M. tuberculosis to rifampicin and isoniazid (MDR-TB) in cultured isolates and clinical samples [7]
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