Summary of the probe development efforts to identify inhibitors of the fructose-bisphosphate aldolase (FBA) of M. tuberculosis
Name: Summary of the probe development efforts to identify inhibitors of the fructose-bisphosphate aldolase (FBA) of M. tuberculosis. ..more
Source (MLPCN Center Name): The Scripps Research Institute Molecular Screening Center (SRISMC)
Center Affiliation: The Scripps Research Institute, TSRI
Assay Provider: Mary Jackson, Colorado State
Network: Molecular Library Probe Production Center Network (MLPCN)
Grant Proposal Number: 1 R21 NS066438-01
Grant Proposal PI: Mary Jackson, Colorado State
External Assay ID: FBA_INH_SUMMARY
Name: Summary of the probe development efforts to identify inhibitors of the fructose-bisphosphate aldolase (FBA) of M. tuberculosis.
The rise in antibiotic-resistant Mycobacterium tuberculosis and the lack of drugs capable of efficiently eradicating persistent bacilli responsible for life-long infections in humans emphasize the need for novel anti-TB agents with mechanisms of action different from those of existing drugs(1, 2). In fact, the latent form of Mycobacterium tuberculosis infects approximately a third of the global population (3). Class II fructose-1, 6-bisphosphate aldolase (FBA) is a key enzyme of glycolysis/gluconeogenesis induced in M. tuberculosis grown under oxygen-limiting conditions thought to mimic the physical microenvironment encountered by persistent bacilli in pulmonary lesions. Fructose bisphosphate aldolase (FBA) catalyzes the conversion of fructose bisphosphate into glyceraldehyde phosphate and dihydroxyacetone phosphate in a reversible fashion. As a result, this enzyme is a likely target for molecular tools to kill multi-drug-resistant as well as persistent M. tuberculosis (2).
Selective inhibition of FBA is expected to prevent M. tuberculosis from growing on host-derived fatty acids during persistent infection. Although ubiquitous in living organisms, FBAs can be divided into two classes which differ in their structure and reaction mechanism. While class I FBAs are the only type found in mammals, prokaryotes produce class II FBAs. The absence of class II FBAs from mammalian cells and the specificity of their structure and catalytic mechanism should make it possible to design specific inhibitors of class II enzymes that target pathogenic bacteria without affecting the host's gluconeogenetic and glycolytic pathways.
Summary of Probe Development Effort:
This probe development effort is focused on the identification of inhibitors of the fructose-bisphosphate aldolase (FBA) of M. tuberculosis. All AIDs that contain results associated with this project can be found in the "Related Bioassays" section of this Summary AID.
1. Siegel, R.E., Emerging gram-negative antibiotic resistance: daunting challenges, declining sensitivities, and dire consequences. Respir Care, 2008. 53(4): p. 471-9.
2. Fonvielle, M., M. Coincon, R. Daher, N. Desbenoit, K. Kosieradzka, N. Barilone, B. Gicquel, J. Sygusch, M. Jackson, and M. Therisod, Synthesis and biochemical evaluation of selective inhibitors of class II fructose bisphosphate aldolases: towards new synthetic antibiotics. Chemistry, 2008. 14(28): p. 8521-9.
3. Pegan, S.D., K. Rukseree, S.G. Franzblau, and A.D. Mesecar, Structural basis for catalysis of a tetrameric class IIa fructose 1,6-bisphosphate aldolase from Mycobacterium tuberculosis. J Mol Biol, 2009. 386(4): p. 1038-53.
Summary, Summary AID, primary, GDH, glycerol phosphate dehydrogenase, bacteria, tuberculosis, M. Tb. TB, infection, aldolase, fructose-bisphosphate aldolase, FBA, NADH, oxidation, NAD, absorbance, abs, inhibition, enzyme, GDH, inhibitor, inhibit, decrease, primary, primary screen, HTS, high throughput screen, 1536, Scripps Florida, The Scripps Research Institute Molecular Screening Center, SRIMSC, Molecular Libraries Probe Production Centers Network, MLPCN.