Investigations on the Biological Costs of Rifampicin Resistance and on the Development of Multidrugresistance in Mycobacterium Tuberculosis

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2004-10

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Addis Ababa University

Abstract

The biological cost of rifampicin resistance mutations in isogenic isolates of a M. tuberculosis strain and the development of multidrug resistance in serial clinical Beijing isolates were studied. Rifampicin is a major drug used in the treatment of tuberculosis. Increasing rifampicin resistance represents a global clinical problem. Most (about 96%) of the resistance to rifampicin is caused by mutations in a small segment of the rpoB gene, which encodes the p-subunit of RNA polymerase. The effect of three different rpoB mutations on the fitness of M. tuberculosis was examined. Rifampicin-resistant mutatnts were initially isolated from a virulent clinical isolate of M. tuberculosis (strain Harlingen) at a mutation frequency of 2.3 x 10'8. Mutations in the rpoB gene were identified by genotypic sequencing and the growth rates of three defined mutants were measured by competition with the susceptible parent strain in laboratory medium and by single cultures in a macrophage cell line and in laboratory medium , All mutants exhibited a decrease in growth rate compared with the susceptible parent in all three assays. The relative fitness of the mutants varied between 0.29 and 0.96 depending on the mutant and assay system used. The results revealed that rifampicin resistance is associated with a cost that is conditional. The Beijing isolates analyzed included eight serial isolates from a single patient in a space of nine years. The RFLP and spoligotype patterns of all these isolates were identical. The results from the Beijing isolates showed that Beijing genotype is associated an increased tendency toward the development of multidrug resistance once resistance to a single first-line drug develops.

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Biology

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