DNA-directed RNA polymerase (Mycobacterium tuberculosis) (RNAP)

Mycobacterial DNA-directed RNA polymerase (RNAP) is a complex multi-subunit enzyme responsible for synthesizing RNA from a DNA template, a process essential for the survival and pathogenesis of Mycobacterium tuberculosis (UniProt: P9WGY9). The enzyme is the primary target of rifamycins, such as rifapentine, which bind to the beta subunit (RpoB) and sterically inhibit the elongation of the nascent RNA chain (PubMed: 33951448). While the input name includes moxifloxacin, this drug actually targets DNA gyrase; however, the combination of rifapentine and moxifloxacin has been clinically validated to shorten tuberculosis treatment duration from six to four months (NEJM: Dorman et al., 2021). Resistance to this target primarily occurs through mutations in the rpoB gene, specifically within the rifampin resistance-determining region (RRDR). Monitoring for these mutations is a standard biomarker for drug-resistant tuberculosis (WHO: Catalogue of mutations in Mycobacterium tuberculosis). Therapeutic use of drugs targeting this polymerase requires careful management of safety concerns, particularly hepatotoxicity and significant drug-drug interactions caused by the induction of hepatic enzymes.

Other names

Mycobacterial RNA polymeraseDNA-dependent RNA polymeraseRNAPRpoBRNA polymerase beta subunit

Rifapentine binds to the beta subunit of the mycobacterial DNA-directed RNA polymerase, physically blocking the path of the elongating RNA transcript and thereby inhibiting protein synthesis (PubMed: 33951448). Moxifloxacin, while often co-administered in this regimen, targets DNA gyrase to inhibit DNA replication (PubChem: CID 152946).