title: Discovery of selective menaquinone biosynthesis inhibitors against Mycobacterium tuberculosis.
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.
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee, 881 Madison, Memphis, Tennessee 38163, USA.
authors.forename: Joy
authors.initials: J
authors.lastname: Debnath
authors.forename: Shajila
authors.initials: S
authors.lastname: Siricilla
authors.forename: Bajoie
authors.initials: B
authors.lastname: Wan
authors.forename: Dean C
authors.initials: DC
authors.lastname: Crick
authors.forename: Anne J
authors.initials: AJ
authors.lastname: Lenaerts
authors.forename: Scott G
authors.initials: SG
authors.lastname: Franzblau
authors.forename: Michio
authors.initials: M
authors.lastname: Kurosu
mesh_terms: D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors*; D000693:Anaerobiosis; D000995:Antitubercular Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors*; D004579:Electron Transport / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D004926:Escherichia coli / Q000187:drug effects; D006898:Hydroxylamines / Q000494:pharmacology; D009169:Mycobacterium tuberculosis / Q000187:drug effects*; D015363:Quinolones / Q000494:pharmacology; D013237:Stereoisomerism; D024482:Vitamin K 2 / Q000031:analogs & derivatives / Q000138:chemical synthesis
chemical_list: D000995:Antitubercular Agents; D001426:Bacterial Proteins; D004791:Enzyme Inhibitors; D006898:Hydroxylamines; D015363:Quinolones; C540754:aurachin RE; D024482:Vitamin K 2; C573554:1,4-dihydroxy-2-naphthoate prenyltransferase, Mycobacterium tuberculosis; D019883:Alkyl and Aryl Transferases