Research Project
6672994
DESCRIPTION (provided by applicant): The communities in the Western Cape of South Africa have one of the highest incidences of tuberculosis in the world with reported outbreaks of drug resistance. This study is based on the observation that the prevalence of INH mono-resistance in local Beijing/W-like drug resistant isolates is high and no gene mutations associated with INH resistance in known genes have yet been identified. It is likely that INH mono-resistance in this family of strains is due to interaction of a combination of bacterial and host risk factors. The overall aim in this pilot study is to identify risk factors associated with Isoniazid resistance which may be pathogen and/or host specific and which may lead to acquisition of MDR-TB in Beijing/W-like strains after controlling for compliance. Two groups of patients will be identified from 72 clinics in the Western Cape. Group 1 will consist of patients infected with drug resistant Beijing/W isolates and group 2 will be patients infected with drug susceptible Beijing/W isolates. The isolates from both groups will then be further phenotypically and genotypically characterized to (i) confirm that the isolates truly belong to the Beijing Family of strains, (ii) identify different clusters as a measure of the propensity of different W-like cluster sizes to develop a drug resistant phenotype and to transmit, (iii) identify Beijing/W isolates with and without INH associated gene mutations as a function of the MIC for INH so that these isolates can be used to identify possible INH induced alterations by protein expression profiling in 2D gels. All patients from groups one and two and a control group without Tuberculosis disease will be retrospectively recruited to give blood to determine the N acetyltransferase allele status, as a measure to metabolize INH in vivo during treatment. In addition, socio-economic, clinical and demographic data will be collected from all patients infected with Beijing/W strains to control for possible confounding. The reference database and well-characterized Beijing/W isolates from this study will lay the foundation to further study the highly prevalent Beijing/W family of strains in local communities. It will also allow comparative analysis to other local outbreak drug resistant strains and will help unravel the mechanisms that lead to the development and spread of drug resistance in local communities.
