Enoyl Reductases as Targets for the Development of Anti-Tubercular and Anti-Malarial Agents

Abstract

Tuberculosis (TB) and Malaria are neglected diseases, which continue to be major causes of morbidity and mortality worldwide, killing together around 5 million people each year. Mycolic acids, the hallmark of mycobacteria, are high-molecular-weight alpha-alkyl, beta-hydroxy fatty acids. Biochemical and genetic experimental data have shown that the product of the M. tuberculosis inhA structural gene (InhA) is the primary target of isoniazid mode of action, the most prescribed anti-tubercular agent. InhA was identified as an NADH-dependent enoyl-ACP(CoA) reductase specific for long-chain enoyl thioesters and is a member of the Type II fatty acid biosynthesis system, which elongates acyl fatty acid precursors of mycolic acids. M. tuberculosis and P. falciparum enoyl reductases are targets for the development of anti-tubercular and antimalarial agents. Here we present a brief description of the mechanism of action of, and resistance to, isoniazid. In addition, data on inhibition of mycobacterial and plasmodial enoyl reductases by triclosan are presented. We also describe recent efforts to develop inhibitors of M. tuberculosis and P. falciparum enoyl reductase enzyme activity.

Dynamics of Plasmodium falciparum enoyl‐ACP reductase and implications on drug discovery

“…A double hydrogen bond between the phenolic ligand hydroxyl group and the phenolic oxygen atom of Tyr182 (Tyr156 in FabI), as well as the 2 0 -hydroxyl group of the nucleotide nicotinamide ribose, is widely considered to be the major contributor to the high affinity of triclosan. 2,6 These two distances were monitored over the course of the relevant simulations and are displayed in Figure 6. Distances between 2.0 and 3.5 Å are representative of hydrogen bonds.…”

“…2 In the process of elongation, a growing fatty acid generally cycles the pathway multiple times until it reaches its final length. Because ENR has been shown to be the ratedetermining step of type II FAS, 6 ENR plays a crucial role in regulating the catalysis of fatty acids 7 and the synthesis of bacterial cell walls. 8 By inhibiting the synthesis of fatty acid by ENR, we envision shutting down Plasmodium falciparum's ability for survival.…”

“…A number of binding features explain the high affinity of TCL: extensive van der Waals contacts in the ternary complex facilitated by the movement of the substrate-binding-loop residues 318-324, 6,14 a phenol ring that makes p-stacking interactions with the NAD þ nicotinamide ring, 2 and hydrogen bonds that form between the phenolic TCL hydroxyl group and both the phenolic oxygen atom of Tyr182 (Tyr156 in FabI) and the 2 0 -hydroxyl group of the nicotinamide ribose. 2,6 Although extensive research has elucidated the structures of ENR in its cofactor and drug bound states, much less is known on the dynamics of this system. 8,[15][16][17] Molecular dynamics (MD) simulations can be used to investigate the dynamics of proteinligand complexes.…”

Novel Inhibitors of InhA Efficiently Kill Mycobacterium tuberculosis under Aerobic and Anaerobic Conditions

“…The inhA gene is essential in mycobacteria, and inhibition of InhA enzymatic activity leads to mycobacterial cell death (39). InhA, as a drug target, has been validated by several studies (5,9,20,24,33,36). GlaxoSmithKline and the TB Alliance have conducted an InhA target-based screen of a million compounds and are in the lead optimization phase (http://www.tballiance.org/new /portfolio/html-portfolio-item.php?idϭ5).…”

Conversion of Quinate to 3-Dehydroshikimate by Ca-Alginate-Immobilized Membrane ofGluconobacter oxydansIFO 3244 and Subsequent Asymmetric Reduction of 3-Dehydroshikimate to Shikimate by Immobilized Cytoplasmic NADP-Shikimate Dehydrogenase

“…A similar strategy can be applied to control parasites as anti-malarial agents. [5][6][7][8][9] In this study, to facilitate the production of metabolic intermediates of pharmaceutical significance in the SKA pathway, immobilization of the membrane fraction of G. oxydans IFO 3244, having the ability to catalyze oxidative fermentation from quinate to DSA, was examined. Immobilization of the cytoplasmic asymmetric reduction system composed of SKDH and GDH was also examined to identify the best carrier for SKA formation from DSA.…”