Mutations in RNA polymerase that drive the emergence of antibiotic resistance

RNA polymerase (RNAP) catalyzes transcription, the first step of gene expression. In bacteria, numerous regulatory proteins and signaling molecules fine-tune RNAP activity in a promoter-specific manner. The resultant changes in gene expression allow cells to acclimate to an ever-changing environment. In addition to phenotypic adaptation, increases in cell fitness can also result from changes in the genome. Here, we explore how mutations in RNAP structural genes benefit cells under diverse selection pressures, with a focus on antibiotics. Selection for resistance to rifampicin (RIF), an antibiotic that binds near the catalytic center of RNAP, leads almost exclusively to amino acid substitutions in the large β subunit that modify the RIF binding site. RIF^R mutations have pleiotropic effects and can lead to increased or decreased sensitivity to other antibiotics. In addition, mutations in RNAP are linked to resistance to β-lactams, antibiotics that target peptidoglycan synthesis. Mutations in RNAP can act by altering the interaction with key regulators, including the sigma (σ) factors required for promoter recognition, transcription factors, or signaling molecules that bind to RNAP. RNAP mutations also affect catalysis with impacts on promoter recognition and clearance, elongation, and termination. We consider illustrative examples of changes in RNAP that alter the transcriptional landscape to facilitate the emergence of antibiotic tolerance and resistance, both in the laboratory and during the clinical course of treatment in patients.