Dynamic Population Changes in Mycobacterium tuberculosis During Acquisition and Fixation of Drug Resistance in Patients

Abstract

Drug-resistant tuberculosis poses a growing challenge to global public health. However, the diversity and dynamics of the bacterial population during acquisition of drug resistance have yet to be carefully examined. Whole-genome sequencing was performed on 7 serial Mycobacterium tuberculosis (M. tuberculosis) populations from 3 patients during different stages in the development of drug resistance. The population diversity was assessed by the number and frequencies of unfixed mutations in each sample. For each bacterial population, 8-41 unfixed mutations were monitored by the fraction of single-nucleotide polymorphisms at specific loci. Among them, as many as 4 to 5 resistance-conferring mutations were transiently detected in the same single sputum, but ultimately only a single type of mutant was fixed. In addition, we identified 14 potential compensatory mutations that occurred during or after the emergence of resistance-conferring mutations. M. tuberculosis population within patients exhibited considerable genetic diversity, which underwent selections for most fit resistant mutant. These findings have important implications and emphasize the need for early diagnosis of tuberculosis to decrease the chance of evolving highly fit drug-resistant strains.