Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 117, Issue 48, Pages 30423-30432Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.2013706117
Keywords
RNA polymerase; sorangicin A; cryo-electron microscopy; multidrug-resistant Mycobacterium tuberculosis; antibiotics
Categories
Funding
- Simons Foundation [SF349247]
- New York State Office of Science, Technology and Academic Research
- NIH National Institute of General Medical Sciences (NIGMS) [GM103310]
- Agouron Institute [F00316]
- NIH [OD019994, R01 GM114450]
- NIH National Center for Research Resources Grant [1S10RR027037]
- NIH NIGMS Grant [P41 GM103403]
- DOE Office of Science [DE-AC02-06CH11357]
- Charles H. Revson Foundation Award [CEN5650030]
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Rifampicin (Rif) is a first-line therapeutic used to treat the infectious disease tuberculosis (TB), which is caused by the pathogen Mycobacterium tuberculosis (Mtb). The emergence of Rif-resistant (RifR) Mtb presents a need for new antibiotics. Rif targets the enzyme RNA polymerase (RNAP). Sorangicin A (Sor) is an unrelated inhibitor that binds in the Rif-binding pocket of RNAP. Sor inhibits a subset of RifR RNAPs, including the most prevalent clinical RifR RNAP substitution found in Mtb infected patients (S456>L of the beta subunit). Here, we present structural and biochemical data demonstrating that Sor inhibits the wild-type Mtb RNAP by a similar mechanism as Rif: by preventing the translocation of very short RNAs. By contrast, Sor inhibits the RifR 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 suit able starting molecule to design drugs to be used for the treatment of TB patients with comorbidities who require multiple medications.
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