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TitleOptimization of Benzoxazinorifamycins to Improve RNA Polymerase Inhibition and Treatment of Tuberculosis.
Journal, issue, pagesACS Infect Dis, Vol. 8, Issue 8, Page 1422-1438, Year 2022
Publish dateAug 12, 2022
AuthorsWalajapet Rajeswaran / Shireen R Ashkar / Pil H Lee / Larisa Yeomans / Yeonoh Shin / Scott G Franzblau / Katsuhiko S Murakami / Hollis D Showalter / George A Garcia /
PubMed AbstractRifampin (RMP), a very potent inhibitor of the (MTB) RNA polymerase (RNAP), remains a keystone in the treatment of tuberculosis since its introduction in 1965. However, rifamycins suffer from ...Rifampin (RMP), a very potent inhibitor of the (MTB) RNA polymerase (RNAP), remains a keystone in the treatment of tuberculosis since its introduction in 1965. However, rifamycins suffer from serious drawbacks, including 3- to 9-month treatment times, Cyp450 induction (particularly problematic for HIV-MTB coinfection), and resistant mutations within RNAP that yield RIF-resistant (RIF) MTB strains. There is a clear and pressing need for improved TB therapies. We have utilized a structure-based drug design approach to synthesize and test novel benzoxazinorifamycins (bxRIF), congeners of the clinical candidate rifalazil. Our goal is to gain binding interactions that will compensate for the loss of RIF-binding affinity to the (RIF) MTB RNAP and couple those with substitutions that we have previously found that essentially eliminate Cyp450 induction. Herein, we report a systematic exploration of 42 substituted bxRIFs that have yielded an analogue () that has an excellent in vitro activity (MTB RNAP inhibition, MIC, MBC), enhanced (∼30-fold > RMP) activity against RIF MTB RNAP, negligible hPXR activation, good mouse pharmacokinetics, and excellent activity with no observable adverse effects in an acute mouse TB model. In a time-kill study, has a 7 day MBC that is ∼10-fold more potent than RMP. These results suggest that may exhibit a faster kill rate than RMP, which could possibly reduce the clinical treatment time. Our synthetic protocol enabled the synthesis of ∼2 g of at >95% purity in 3 months, demonstrating the feasibility of scale-up synthesis of bxRIFs for preclinical and clinical studies.
External linksACS Infect Dis / PubMed:35772744
MethodsEM (single particle)
Resolution2.94 - 3.11 Å
Structure data

25570

7szj

EMDB-25570, PDB-7szj:
Cryo-EM structure of Rifamycin bound to E. coli RNAP and rrnBP1 promoter complex
Method: EM (single particle) / Resolution: 3.11 Å

25571

7szk

EMDB-25571, PDB-7szk:
Cryo-EM structure of 27a bound to E. coli RNAP and rrnBP1 promoter complex
Method: EM (single particle) / Resolution: 2.94 Å

Chemicals

ChemComp-RFP:
RIFAMPICIN / antibiotic*YM

ChemComp-MG:
Unknown entry

ChemComp-ZN:
Unknown entry

ChemComp-D9X:
(2S,7R,7aR,13aP,16Z,18E,20S,21S,22R,23R,24R,25S,26R,27S,28E)-5,21,23-trihydroxy-27-methoxy-2,4,16,20,22,24,26-heptamethyl-10-[4-(2-methylpropyl)piperazin-1-yl]-12-({4-[(morpholin-4-yl)methyl]phenyl}methoxy)-1,6,15-trioxo-1,2,7,7a-tetrahydro-6H-2,7-(epoxypentadeca[1,11,13]trienoimino)[1]benzofuro[4,5-a]phenoxazin-25-yl acetate

Source
  • escherichia coli k-12 (bacteria)
KeywordsTRANSFERASE/DNA/ANTIBIOTIC / Transcription / antibiotics / Rifamycin / TRANSFERASE-DNA-ANTIBIOTIC complex

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