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The antibiotic sorangicin A inhibits promoter DNA unwinding in a rifampicin-resistant RNA polymerase.
Lilic, Mirjana Chen, James Boyaci, Hande Braffman, Nathaniel Hubin, Elizabeth A Herrmann, Jennifer Müller, Rolf Mooney, Rachel Landick, Robert Darst, Seth A
Lilic, Mirjana
Chen, James
Boyaci, Hande
Braffman, Nathaniel
Hubin, Elizabeth A
Herrmann, Jennifer
Müller, Rolf
Mooney, Rachel
Landick, Robert
Darst, Seth A
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2020-11-16
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Abstract
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). 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 suitable starting molecule to design drugs to be used for the treatment of TB patients with comorbidities who require multiple medications.
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Proc Natl Acad Sci U S A. 2020 Dec 1;117(48):30423-30432. doi: 10.1073/pnas.2013706117. Epub 2020 Nov.
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Article
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en
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1091-6490
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Attribution-NonCommercial-ShareAlike 4.0 International