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: Gerald L Newton, Nancy Buchmeier, James J La Clair, Robert C Fahey
• Journal: Bioorganic & medicinal chemistry (Bioorg Med Chem) Vol. 19 Issue 13 Pg. 3956-64 (Jul 01 2011) ISSN: 1464-3391 [Electronic] England
• PMID: 21665483 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: Copyright © 2011 Elsevier Ltd. All rights reserved.

Chemical References

• Bacterial Proteins
• Dibenzothiazepines
• Enzyme Inhibitors
• Glycopeptides
• NTF 1836
• mycothiol
• Inositol
• Cysteine

Topics

• Animals
• Bacterial Proteins (antagonists & inhibitors, metabolism)
• Chlorocebus aethiops
• Cysteine (biosynthesis)
• Dibenzothiazepines (chemical synthesis, chemistry, toxicity)
• Drug Evaluation, Preclinical
• Enzyme Inhibitors (chemical synthesis, chemistry, toxicity)
• Glycopeptides (biosynthesis)
• Inositol (biosynthesis)
• Mycobacterium tuberculosis (drug effects, enzymology)
• Structure-Activity Relationship
• Vero Cells