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

Jun-Hao Zhu, Bi-Wei Wang, Miaomiao Pan, Yu-Na Zeng, Hesper Rego and Babak Javid ()
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Jun-Hao Zhu: Tsinghua University School of Medicine
Bi-Wei Wang: Tsinghua University School of Medicine
Miaomiao Pan: Tsinghua University School of Medicine
Yu-Na Zeng: Tsinghua University School of Medicine
Hesper Rego: Yale School of Medicine
Babak Javid: Tsinghua University School of Medicine

Nature Communications, 2018, vol. 9, issue 1, 1-13

Abstract: Abstract 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 rpoB upregulation in a sub-population of cells, followed by growth. More specifically, rifampicin preferentially inhibits one of the two rpoB promoters (promoter I), allowing increased rpoB 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 rpoB expression to tolerance.

Date: 2018
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DOI: 10.1038/s41467-018-06667-3

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