Conjugates of plumbagin and phenyl-2-amino-1-thioglucoside inhibit MshB, a deacetylase involved in the biosynthesis of mycothiol

David W Gammon; Daniel J Steenkamp; Vuyo Mavumengwana; Mohlopheni J Marakalala; Theophilus T Mudzunga; Roger Hunter; Muganza Munyololo

doi:10.1016/j.bmc.2010.02.049

Conjugates of plumbagin and phenyl-2-amino-1-thioglucoside inhibit MshB, a deacetylase involved in the biosynthesis of mycothiol

Bioorg Med Chem. 2010 Apr 1;18(7):2501-14. doi: 10.1016/j.bmc.2010.02.049. Epub 2010 Mar 1.

Authors

David W Gammon¹, Daniel J Steenkamp, Vuyo Mavumengwana, Mohlopheni J Marakalala, Theophilus T Mudzunga, Roger Hunter, Muganza Munyololo

Affiliation

¹ Department of Chemistry, University of Cape Town, Rondebosch 7701, South Africa. david.gammon@uct.ac.za

PMID: 20304659
DOI: 10.1016/j.bmc.2010.02.049

Abstract

N-Acetylglucosaminylinositol (GlcNAc-Ins)-deacetylase (MshB) and mycothiol-S-conjugate amidase (Mca), structurally related amidases present in mycobacteria and other Actinomycetes, are involved in the biosynthesis of mycothiol and in the detoxification of xenobiotics as their mycothiol-S-conjugates, respectively. With substrate analogs of GlcNAc-Ins, MshB showed a marked preference for inositol as the aglycon present in GlcNAc-Ins. The inhibition of MshB and Mca by 10 thioglycosides, 7 cyclohexyl-2-deoxy-2-C-alkylglucosides, and 4 redox cyclers was evaluated. The latter contained plumbagin tethered via 2 to 5 methylene carbons and an amide linkage to phenyl-2-deoxy-2-amino-1-thio-alpha-d-glucopyranoside. These proved to be the most potent amongst the 21 compounds tested as inhibitors of MshB. Their inhibitory potency varied with the length of the spacer, with the compound with longest spacer being the most effective.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Acetylcysteine / chemistry
Amidohydrolases / antagonists & inhibitors*
Amidohydrolases / isolation & purification
Bacterial Proteins / antagonists & inhibitors*
Bacterial Proteins / isolation & purification
Cell Survival
Cysteine / biosynthesis*
Enzyme Inhibitors / chemical synthesis*
Enzyme Inhibitors / pharmacology*
Glycopeptides / biosynthesis*
Indicators and Reagents
Inositol / biosynthesis*
Inositol / chemistry
Mycobacterium tuberculosis / enzymology
NADH, NADPH Oxidoreductases / antagonists & inhibitors
Naphthoquinones / chemistry*
Naphthoquinones / pharmacology*
Oxidation-Reduction
Structure-Activity Relationship
Substrate Specificity
Thioglucosides / chemical synthesis
Thioglucosides / pharmacology

Substances

Bacterial Proteins
Enzyme Inhibitors
Glycopeptides
Indicators and Reagents
Naphthoquinones
Thioglucosides
mycothiol
Inositol
NADH, NADPH Oxidoreductases
disulfide reductase, mycothiol
Amidohydrolases
N-acetyl-1-D-inosityl-2-amino-2-deoxy-alpha-D-glucopyranoside deacetylase
mycothiol S-conjugate amidase
Cysteine
Acetylcysteine
plumbagin