The antibiotic sorangicin A inhibits promoter DNA unwinding in a <i>Mycobacterium tuberculosis</i> rifampicin-resistant RNA polymerase
Mirjana Lilić, James Chen, Hande Boyaci, Nathaniel R. Braffman, Elizabeth A. Hubin, Jennifer Herrmann, Rolf Müller, Rachel A. Mooney, Robert Landick, Seth A. Darst, Elizabeth A. Campbell
Abstract
S456L enzyme at an earlier step, preventing the transition of a partially unwound promoter DNA intermediate to the fully opened DNA and blocking the template-strand DNA from reaching the active site in the RNAP catalytic center. By defining template-strand blocking as a mechanism for inhibition, we provide a mechanistic drug target in RNAP. Our finding that Sor inhibits the wild-type and mutant RNAPs through different mechanisms prompts future considerations for designing antibiotics against resistant targets. Also, we show that Sor has a better pharmacokinetic profile than Rif, making it a suitable starting molecule to design drugs to be used for the treatment of TB patients with comorbidities who require multiple medications.