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TitleThe antibiotic sorangicin A inhibits promoter DNA unwinding in a rifampicin-resistant RNA polymerase.
Journal, issue, pagesProc Natl Acad Sci U S A, Vol. 117, Issue 48, Page 30423-30432, Year 2020
Publish dateDec 1, 2020
AuthorsMirjana Lilic / James Chen / Hande Boyaci / Nathaniel Braffman / Elizabeth A Hubin / Jennifer Herrmann / Rolf Müller / Rachel Mooney / Robert Landick / Seth A Darst / Elizabeth A Campbell /
PubMed AbstractRifampicin (Rif) is a first-line therapeutic used to treat the infectious disease tuberculosis (TB), which is caused by the pathogen (). The emergence of Rif-resistant (Rif) presents a need for new ...Rifampicin (Rif) is a first-line therapeutic used to treat the infectious disease tuberculosis (TB), which is caused by the pathogen (). The emergence of Rif-resistant (Rif) 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 Rif RNAPs, including the most prevalent clinical Rif RNAP substitution found in infected patients (S456>L of the β subunit). Here, we present structural and biochemical data demonstrating that Sor inhibits the wild-type RNAP by a similar mechanism as Rif: by preventing the translocation of very short RNAs. By contrast, Sor inhibits the Rif 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.
External linksProc Natl Acad Sci U S A / PubMed:33199626 / PubMed Central
MethodsEM (single particle) / X-ray diffraction
Resolution2.901 - 4.38 Å
Structure data

21406

6vvx

EMDB-21406, PDB-6vvx:
Mycobacterium tuberculosis WT RNAP transcription initiation intermediate structure with Sorangicin
Method: EM (single particle) / Resolution: 3.39 Å

21407

6vvy

EMDB-21407, PDB-6vvy:
Mycobacterium tuberculosis WT RNAP transcription open promoter complex with Sorangicin
Method: EM (single particle) / Resolution: 3.42 Å

21408

6vvz

EMDB-21408, PDB-6vvz:
Mycobacterium tuberculosis RNAP S456L mutant transcription initiation intermediate structure with Sorangicin
Method: EM (single particle) / Resolution: 3.72 Å

21409

6vw0

EMDB-21409, PDB-6vw0:
Mycobacterium tuberculosis RNAP S456L mutant open promoter complex
Method: EM (single particle) / Resolution: 3.59 Å

EMDB-22573:
Mycobacterium tuberculosis Wildtype-RNAP holoenzyme/RbpA/CarD/Sor/AP3 - PreRP2 class
Method: EM (single particle) / Resolution: 4.26 Å

EMDB-22575:
Mycobacterium tuberculosis Wildtype-RNAP holoenzyme/RbpA/CarD/Sor/AP3 - RP2 class
Method: EM (single particle) / Resolution: 3.53 Å

EMDB-22577:
Mycobacterium tuberculosis Wildtype-RNAP holoenzyme/RbpA/CarD/Sor/AP3 - RPo class
Method: EM (single particle) / Resolution: 3.35 Å

EMDB-22578:
Mycobacterium tuberculosis BetaS456L-RNAP holoenzyme/RbpA/CarD/Sor/AP3 - PreRP2 class
Method: EM (single particle) / Resolution: 4.38 Å

EMDB-22579:
Mycobacterium tuberculosis BetaS456L-RNAP holoenzyme/RbpA/CarD/Sor/AP3 - RP2 class
Method: EM (single particle) / Resolution: 3.69 Å

EMDB-22580:
Mycobacterium tuberculosis BetaS456L-RNAP holoenzyme/RbpA/CarD/Sor/AP3 - RPo class
Method: EM (single particle) / Resolution: 3.74 Å

PDB-6vvs:
Crystal structure of a Mycobacterium smegmatis RNA polymerase transcription initiation complex with antibiotic Sorangicin
Method: X-RAY DIFFRACTION / Resolution: 3.112 Å

PDB-6vvt:
Crystal structure of a Mycobacterium smegmatis transcription initiation complex with Rifampicin-resistant RNA polymerase and antibiotic Sorangicin
Method: X-RAY DIFFRACTION / Resolution: 2.901 Å

PDB-6vvv:
Crystal structure of a Mycobacterium smegmatis transcription initiation complex with Rifampicin-resistant RNA polymerase
Method: X-RAY DIFFRACTION / Resolution: 3.2 Å

Chemicals

ChemComp-SO4:
SULFATE ION

ChemComp-EDO:
1,2-ETHANEDIOL

ChemComp-SRN:
SORANGICIN A

ChemComp-ZN:
Unknown entry

ChemComp-HOH:
WATER

ChemComp-MG:
Unknown entry

Source
  • mycobacterium tuberculosis (bacteria)
  • mycolicibacterium smegmatis (strain atcc 700084 / mc(2)155) (bacteria)
  • synthetic construct (others)
KeywordsTRANSCRIPTION / TRANSFERASE/DNA/ANTIBIOTIC / DNA binding / antibiotic / TRANSFERASE-DNA-ANTIBIOTIC complex / TRANSFERASE/DNA / TRANSFERASE-DNA complex / initiation / transcription bubble / sorangicin / open promoter complex

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