The antibiotic sorangicin A inhibits promoter DNA unwinding in a Mycobacterium tuberculosis rifampicin-resistant RNA polymerase
| Autor: | Rolf Müller, Robert Landick, Mirjana Lilic, Jennifer Herrmann, Rachel A. Mooney, Hande Boyaci, Elizabeth A. Campbell, Nathaniel Braffman, James Chen, Seth A. Darst, Elizabeth A. Hubin |
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| Rok vydání: | 2020 |
| Předmět: |
chemistry.chemical_classification
Multidisciplinary biology Mutant Promoter bacterial infections and mycoses biology.organism_classification Microbiology Mycobacterium tuberculosis enzymes and coenzymes (carbohydrates) chemistry.chemical_compound Enzyme chemistry RNA polymerase medicine bacteria Multidrug-Resistant Mycobacterium tuberculosis DNA Rifampicin medicine.drug |
| Zdroj: | Proceedings of the National Academy of Sciences. 117:30423-30432 |
| ISSN: | 1091-6490 0027-8424 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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