The antibiotic sorangicin A inhibits promoter DNA unwinding in a rifampicin-resistant RNA polymerase.
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Authors
Lilic, MirjanaChen, James
Boyaci, Hande
Braffman, Nathaniel
Hubin, Elizabeth A
Herrmann, Jennifer
Müller, Rolf
Mooney, Rachel
Landick, Robert
Darst, Seth A
Campbell, Elizabeth A
Issue Date
2020-11-16
Metadata
Show full item recordAbstract
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.Citation
Proc Natl Acad Sci U S A. 2020 Dec 1;117(48):30423-30432. doi: 10.1073/pnas.2013706117. Epub 2020 Nov.Affiliation
HIPS, Helmholtz-Institut für Pharmazeutische Forschung Saarland, Universitätscampus E8.1 66123 Saarbrücken, Germany.Publisher
National Academy of SciencesPubMed ID
33199626Type
ArticleLanguage
enEISSN
1091-6490ae974a485f413a2113503eed53cd6c53
10.1073/pnas.2013706117
Scopus Count
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