Journal
EUROPEAN JOURNAL OF PHARMACOLOGY
Volume 694, Issue 1-3, Pages 45-52Publisher
ELSEVIER
DOI: 10.1016/j.ejphar.2012.08.012
Keywords
4-diphosphocytidyl-2-C-methyl-D-erythritol synthase (CDP-MEP synthase, IspD); Inhibitor; DMB (Domiphen bromide); Antituberculosis activity; Target
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Funding
- Important National Science and Technology Special Projects of China during the 11th Five-Year Plan [2008ZX10003006]
- National Natural Science Foundation of China [30873186NST, 81072674NST]
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Tuberculosis is a serious threat to world-wide public health usually caused in humans by Mycobacterium tuberculosis (M. tuberculosis). It exclusively utilizes the methylerythritol phosphate (MEP) pathway for biosynthesis of isopentenyl diphosphate (IPP) and its isomer dimethylallyl diphosphate (DMAPP), the precursors of all isoprenoid compounds. The 4-diphosphocytidyl-2-C-methyl-D-erythritol synthase (IspD; EC 2.7.7.60) is the key enzyme of the MEP pathway. It is also of interest as a new chemotherapeutic target, as the enzyme is absent in mammals and ispD is an essential gene for growth. A high-throughput screening method was therefore developed to identify compounds that inhibit IspD. This process was applied to identify a lead compound, domiphen bromide (DMB), that may effectively inhibit IspD. The inhibitory action of DMB was confirmed by over-expressing or down-regulating IspD in Mycobacterium smegmatis (M. smegmatis), demonstrating that DMB inhibit M. smegmatis growth additionally through an IspD-independent pathway. This also led to higher levels of growth inhibition when combined with IspD knockdown. This novel IspD inhibitor was also reported to exhibit antimycobacterial activity in vitro, an effect that likely occurs as a result of perturbation of cell wall biosynthesis. (c) 2012 Elsevier B.V. All rights reserved.
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