title: Evaluation of NTF1836 as an inhibitor of the mycothiol biosynthetic enzyme MshC in growing and non-replicating Mycobacterium tuberculosis.
abstract: The mycothiol biosynthesis enzyme MshC catalyzes the ligation of cysteine with the pseudodisaccharide GlcN-Ins and has been identified as an essential enzyme in Mycobacterium tuberculosis. We now report on the development of NTF1836 as a micromolar inhibitor of MshC. Using commercial libraries, we conducted preliminary structure-activity relationship (SAR) studies on NTF1836. Based on this data, NTF1836 and five structurally related compounds showed similar activity towards clinical strains of M. tuberculosis. A gram scale synthesis was developed to provide ample material for biological studies. Using this material, we determined that inhibition of M. tuberculosis growth by NTF1836 was accompanied by a fall in mycothiol and an increase in GlcN-Ins consistent with the targeting of MshC. We also determined that NTF1836 kills non-replicating M. tuberculosis in the carbon starvation model of latency.
authors.affiliation: Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, CA 92093-0314, United States.
authors.forename: Gerald L
authors.initials: GL
authors.lastname: Newton
authors.forename: Nancy
authors.initials: N
authors.lastname: Buchmeier
authors.forename: James J
authors.initials: JJ
authors.lastname: La Clair
authors.forename: Robert C
authors.initials: RC
authors.lastname: Fahey
mesh_terms: D000818:Animals; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D002522:Chlorocebus aethiops; D003545:Cysteine / Q000096:biosynthesis; D003987:Dibenzothiazepines / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity; D006020:Glycopeptides / Q000096:biosynthesis; D007294:Inositol / Q000096:biosynthesis; D009169:Mycobacterium tuberculosis / Q000187:drug effects / Q000201:enzymology*; D013329:Structure-Activity Relationship; D014709:Vero Cells
chemical_list: D001426:Bacterial Proteins; D003987:Dibenzothiazepines; D004791:Enzyme Inhibitors; D006020:Glycopeptides; C561756:NTF 1836; C089265:mycothiol; D007294:Inositol; D003545:Cysteine