Journal
BIOORGANIC & MEDICINAL CHEMISTRY
Volume 11, Issue 4, Pages 601-608Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/S0968-0896(02)00345-0
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The current rise in mycobacterial-related infections and disease, coupled with drug resistance, underlines the continuing need for new antimycobacterials. To this end, we have screened similar to1500 extracts derived from marine plants and invertebrates and terrestrial fungi for their ability to inhibit a newly described mycobacterial detoxification enzyme mycothiol-S-conjugate amidase (MCA). As described in this paper, our screening and chemistry efforts thus far have led to the identification of 13 natural product inhibitors that represent six different structural classes. By conducting enzyme inhibition assays using varied inhibitor and substrate concentrations, we have determined the mode of inhibition of Mycobacterium tuberculosis MCA for four of these compounds. We show that two types of bromo tyro sine-derived natural products are competitive inhibitors of MCA; while oceanapiside, an alpha,omega-bisaminohydroxy glycosphingolipid, and the fungal metabolite gliotoxin, a dithiadiketopiperazine, are simple and mixed non-competitive inhibitors, respectively. Correlation of these results with the chemical structures suggests that MCA is a metalloenzyme and that the oximinoamide and spiro-isoxazoline amide groups present in the competitive inhibitors are substrate mimics. (C) 2002 Elsevier Science Ltd. All rights reserved.
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