Rifampicin can induce antibiotic tolerance in mycobacteria via paradoxical changes in rpoB transcription

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<jats:title>Abstract</jats:title><jats:p>Metrics commonly used to describe antibiotic efficacy rely on measurements performed on bacterial populations. However, certain cells in a bacterial population can continue to grow and divide, even at antibiotic concentrations that kill the majority of cells, in a phenomenon known as antibiotic tolerance. Here, we describe a form of semi-heritable tolerance to the key anti-mycobacterial agent rifampicin, which is known to inhibit transcription by targeting the β subunit of the RNA polymerase (RpoB). We show that rifampicin exposure results in <jats:italic>rpoB</jats:italic> upregulation in a sub-population of cells, followed by growth. More specifically, rifampicin preferentially inhibits one of the two <jats:italic>rpoB</jats:italic> promoters (promoter I), allowing increased <jats:italic>rpoB</jats:italic> expression from a second promoter (promoter II), and thus triggering growth. Disruption of promoter architecture leads to differences in rifampicin susceptibility of the population, confirming the contribution of rifampicin-induced <jats:italic>rpoB</jats:italic> expression to tolerance.</jats:p>

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