The antibiotic sorangicin A inhibits promoter DNA unwinding in a Mycobacterium tuberculosis rifampicin-resistant RNA polymerase
- Rockefeller Univ., New York, NY (United States)
- Saarland Univ., Saarbrücken (Germany); Center for Infection Research, Braunschweig (Germany)
- Univ. of Wisconsin, Madison, WI (United States)
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 β subunit). In this paper, 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 suitable starting molecule to design drugs to be used for the treatment of TB patients with comorbidities who require multiple medications.
- Research Organization:
- Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
- Sponsoring Organization:
- Simons Foundation; New York State Office of Science,Technology and Academic Research; National institutes of Health (NIH); National Institute of General Medical Sciences (NIGMS); Agouron Institute; USDOE Office of Science (SC); The Charles H. Revson Foundation
- Grant/Contract Number:
- SF349247; GM103310; F00316; OD019994; 1S10RR027037; P41 GM103403; AC02-06CH11357; R01 GM114450; CEN5650030
- OSTI ID:
- 1763105
- Journal Information:
- Proceedings of the National Academy of Sciences of the United States of America, Vol. 117, Issue 48; ISSN 0027-8424
- Publisher:
- National Academy of SciencesCopyright Statement
- Country of Publication:
- United States
- Language:
- ENGLISH
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