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dc.contributor.authorLilic, Mirjana
dc.contributor.authorChen, James
dc.contributor.authorBoyaci, Hande
dc.contributor.authorBraffman, Nathaniel
dc.contributor.authorHubin, Elizabeth A
dc.contributor.authorHerrmann, Jennifer
dc.contributor.authorMüller, Rolf
dc.contributor.authorMooney, Rachel
dc.contributor.authorLandick, Robert
dc.contributor.authorDarst, Seth A
dc.contributor.authorCampbell, Elizabeth A
dc.date.accessioned2020-12-15T16:07:50Z
dc.date.available2020-12-15T16:07:50Z
dc.date.issued2020-11-16
dc.identifier.citationProc Natl Acad Sci U S A. 2020 Dec 1;117(48):30423-30432. doi: 10.1073/pnas.2013706117. Epub 2020 Nov.en_US
dc.identifier.pmid33199626
dc.identifier.doi10.1073/pnas.2013706117
dc.identifier.urihttp://hdl.handle.net/10033/622656
dc.description.abstractRifampicin (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.en_US
dc.language.isoenen_US
dc.publisherNational Academy of Sciencesen_US
dc.rightsAttribution-NonCommercial-ShareAlike 4.0 International*
dc.rights.urihttp://creativecommons.org/licenses/by-nc-sa/4.0/*
dc.subjectRNA polymeraseen_US
dc.subjectantibioticsen_US
dc.subjectcryo-electron microscopyen_US
dc.subjectmultidrug-resistant Mycobacterium tuberculosisen_US
dc.subjectsorangicin Aen_US
dc.titleThe antibiotic sorangicin A inhibits promoter DNA unwinding in a rifampicin-resistant RNA polymerase.en_US
dc.typeArticleen_US
dc.identifier.eissn1091-6490
dc.contributor.departmentHIPS, Helmholtz-Institut für Pharmazeutische Forschung Saarland, Universitätscampus E8.1 66123 Saarbrücken, Germany.en_US
dc.identifier.journalProceedings of the National Academy of Sciences of the United States of Americaen_US
dc.source.volume117
dc.source.issue48
dc.source.beginpage30423
dc.source.endpage30432
dc.source.journaltitleProceedings of the National Academy of Sciences of the United States of America
dc.source.countryUnited States


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