Physiological Cost of Rifampin Resistance Induced In Vitro in Mycobacterium tuberculosis

Abstract

ABSTRACT Drug-resistant Mycobacterium tuberculosis is a major threat to public health. In clinical practice, a limited number of resistance mutations in a short sequence of the beta subunit of RNA polymerase (encoded by rpoB ) have been described. Spontaneous resistance to rifampin was induced in vitro in M. tuberculosis H37Rv (ATCC 9360). Only three resistance patterns could be detected by PCR–single-strand conformation polymorphism analysis. Sequence analysis revealed that Ser 531 →Leu arose most frequently, followed by His 526 →Arg and then either His 526 →Tyr or His 526 →Asp. The relative Darwinian fitness of all but one of the mutant genotypes was less than that of the susceptible parent and, for these mutations, there was a significant correlation between fitness and clinical isolation rate (regression analysis P = 0.026). The fitness deficit in some mutants was small, suggesting that there is little likelihood of a spontaneous reversion to susceptibility.