Discovery of selective menaquinone biosynthesis inhibitors against Mycobacterium tuberculosis

Joy Debnath, Shajila Siricilla, Bajoie Wan, Dean C. Crick, Anne J. Lenaerts, Scott G. Franzblau, Michio Kurosu

Research output: Contribution to journalArticle

54 Citations (Scopus)

Abstract

Aurachin RE (1) is a strong antibiotic that was recently found to possess 1,4-dihydroxy-2-naphthoate prenyltransferase (MenA) and bacterial electron transport inhibitory activities. Aurachin RE is the only molecule in a series of aurachin natural products that has the chiral center in the alkyl side chain at C9′-position. To identify selective MenA inhibitors against Mycobacterium tuberculosis, a series of chiral molecules were designed based on the structures of previously identified MenA inhibitors and 1. The synthesized molecules were evaluated in in vitro assays, including MenA enzyme and bacterial growth inhibitory assays. We could identify novel MenA inhibitors that showed significant increase in potency of killing nonreplicating M. tuberculosis in the low oxygen recovery assay (LORA) without inhibiting other Gram-positive bacterial growth even at high concentrations. The MenA inhibitors reported here are useful new pharmacophores for the development of selective antimycobacterial agents with strong activity against nonreplicating M. tuberculosis.

Original languageEnglish (US)
Pages (from-to)3739-3755
Number of pages17
JournalJournal of Medicinal Chemistry
Volume55
Issue number8
DOIs
StatePublished - Apr 26 2012

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Vitamin K 2
Mycobacterium tuberculosis
Dimethylallyltranstransferase
Anti-Bacterial Agents
Growth
Electron Transport
Biological Products
Oxygen
Enzymes
aurachin RE

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Drug Discovery

Cite this

Debnath, J., Siricilla, S., Wan, B., Crick, D. C., Lenaerts, A. J., Franzblau, S. G., & Kurosu, M. (2012). Discovery of selective menaquinone biosynthesis inhibitors against Mycobacterium tuberculosis. Journal of Medicinal Chemistry, 55(8), 3739-3755. https://doi.org/10.1021/jm201608g

Discovery of selective menaquinone biosynthesis inhibitors against Mycobacterium tuberculosis. / Debnath, Joy; Siricilla, Shajila; Wan, Bajoie; Crick, Dean C.; Lenaerts, Anne J.; Franzblau, Scott G.; Kurosu, Michio.

In: Journal of Medicinal Chemistry, Vol. 55, No. 8, 26.04.2012, p. 3739-3755.

Research output: Contribution to journalArticle

Debnath, J, Siricilla, S, Wan, B, Crick, DC, Lenaerts, AJ, Franzblau, SG & Kurosu, M 2012, 'Discovery of selective menaquinone biosynthesis inhibitors against Mycobacterium tuberculosis', Journal of Medicinal Chemistry, vol. 55, no. 8, pp. 3739-3755. https://doi.org/10.1021/jm201608g
Debnath J, Siricilla S, Wan B, Crick DC, Lenaerts AJ, Franzblau SG et al. Discovery of selective menaquinone biosynthesis inhibitors against Mycobacterium tuberculosis. Journal of Medicinal Chemistry. 2012 Apr 26;55(8):3739-3755. https://doi.org/10.1021/jm201608g
Debnath, Joy ; Siricilla, Shajila ; Wan, Bajoie ; Crick, Dean C. ; Lenaerts, Anne J. ; Franzblau, Scott G. ; Kurosu, Michio. / Discovery of selective menaquinone biosynthesis inhibitors against Mycobacterium tuberculosis. In: Journal of Medicinal Chemistry. 2012 ; Vol. 55, No. 8. pp. 3739-3755.
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