Compensatory evolution in NusG improves fitness of drug-resistant M. tuberculosis

Kathryn A. Eckartt, Madeleine Delbeau, Vanisha Munsamy-Govender, Michael A. DeJesus, Zachary A. Azadian, Abhijna K. Reddy, Joshua Chandanani, Nicholas C. Poulton, Stefany Quiñones-Garcia, Barbara Bosch, Robert Landick, Elizabeth A. Campbell () and Jeremy M. Rock ()
Additional contact information
Kathryn A. Eckartt: The Rockefeller University
Madeleine Delbeau: The Rockefeller University
Vanisha Munsamy-Govender: The Rockefeller University
Michael A. DeJesus: The Rockefeller University
Zachary A. Azadian: The Rockefeller University
Abhijna K. Reddy: The Rockefeller University
Joshua Chandanani: The Rockefeller University
Nicholas C. Poulton: The Rockefeller University
Stefany Quiñones-Garcia: The Rockefeller University
Barbara Bosch: The Rockefeller University
Robert Landick: University of Wisconsin–Madison
Elizabeth A. Campbell: The Rockefeller University
Jeremy M. Rock: The Rockefeller University

Nature, 2024, vol. 628, issue 8006, 186-194

Abstract: Abstract Drug-resistant bacteria are emerging as a global threat, despite frequently being less fit than their drug-susceptible ancestors1–8. Here we sought to define the mechanisms that drive or buffer the fitness cost of rifampicin resistance (RifR) in the bacterial pathogen Mycobacterium tuberculosis (Mtb). Rifampicin inhibits RNA polymerase (RNAP) and is a cornerstone of modern short-course tuberculosis therapy9,10. However, RifR Mtb accounts for one-quarter of all deaths due to drug-resistant bacteria11,12. We took a comparative functional genomics approach to define processes that are differentially vulnerable to CRISPR interference (CRISPRi) inhibition in RifR Mtb. Among other hits, we found that the universally conserved transcription factor NusG is crucial for the fitness of RifR Mtb. In contrast to its role in Escherichia coli, Mtb NusG has an essential RNAP pro-pausing function mediated by distinct contacts with RNAP and the DNA13. We find this pro-pausing NusG–RNAP interface to be under positive selection in clinical RifR Mtb isolates. Mutations in the NusG–RNAP interface reduce pro-pausing activity and increase fitness of RifR Mtb. Collectively, these results define excessive RNAP pausing as a molecular mechanism that drives the fitness cost of RifR in Mtb, identify a new mechanism of compensation to overcome this cost, suggest rational approaches to exacerbate the fitness cost, and, more broadly, could inform new therapeutic approaches to develop drug combinations to slow the evolution of RifR in Mtb.

Date: 2024
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DOI: 10.1038/s41586-024-07206-5

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