RNA polymerase-mediated regulation of intrinsic antibiotic resistance and bacterial cell division

Rifampin is a frontline antibiotic that inhibits the RNA polymerase of Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB). Unlike most antibiotics, rifampin has an unusual ability to shorten the duration of treatment needed to cure TB that is not simply explained by its antimicrobial potency. We sought specific secondary effects of rifampin’s inhibition of Mtb RNA polymerase that may mediate this activity. We discovered that rifampin elicited a cell division arrest that was mediated through its inhibition of RNA polymerase. This arrest resulted in a downstream inhibition of the MtrAB two-component regulatory system, a mediator of intrinsic antibiotic resistance in Mtb. This inhibition is broadly conserved in other bacteria and represents a novel form of antimicrobial activity, termed adjunctive sensitization, that can mediate synergy and may contribute to rifampin’s unusual treatment shortening activity.