Three classes of inhibitors are based on isoniazid, the diazaborines and triclosan, antibacterial agents that were subsequently shown to inhibit InhA
Three classes of inhibitors are based on isoniazid, the diazaborines and triclosan, antibacterial agents that were subsequently shown to inhibit InhA. (C60-C90) fatty acids that are important for the ability of to live and replicate inside macrophages, and also for the inability of many antibiotics to penetrate into the cytosol [1-2]. Consequently, compounds that antagonize the ability of mycobacteria to synthesize mycolic acids are encouraging prospects for developing novel tuberculosis chemotherapeutics. The Atuveciclib (BAY-1143572) fatty acid precursors required for mycolic acid synthesis are generated by the mycobacterial type I (FASI) and type II (FASII) biosynthetic pathways (Fig. (1)). The FASI enzyme complex, which is usually homologous to the synthase found in mammalian cells, catalyzes the de novo synthesis of C20-C24 fatty acyl-CoAs that are subsequently extended by the FASII system producing fatty acids up to C56 in length. Open in a separate windows Fig. (1) Fatty acid biosynthesis in is sometimes referred to as AcpM. In addition, since InhA is usually a FabI enoyl-ACP reductase, this enzyme is sometimes referred to as the FabI from and, by extension, Gram positive bacteria in general [3]. While doubt has now been cast around the generality of the conclusions reached in this study, at least with regard to the important nosocomial pathogen [4], it is important to note that mammals do not synthesize mycolic acids and thus the FASII pathway must play an essential role in mycobacteria. This belief is usually supported by the knowledge that the very effective front-line drug isoniazid targets InhA, the enoyl-ACP reductase in the FASII pathway Atuveciclib (BAY-1143572) [5-9], while Jacobs and coworkers have exhibited that inactivation of InhA in results in cell lysis [10]. The primary mechanism of resistance to isoniazid occurs from mutations in the mycobacterial catalase peroxidase enzyme KatG that is responsible for drug activation and not from mutations Atuveciclib (BAY-1143572) in Atuveciclib (BAY-1143572) InhA [11-12]. Consequently, inhibitors of InhA that do not require KatG activation should be active against most clinical strains of isoniazid-resistant [13]. InhA is usually a member of the short chain dehydrogenase reductase superfamily and is in the FabI class of enoyl-ACP reductases that are found in bacteria such as and [7, 14]. Given the continuing need to develop antibacterial brokers with novel mechanisms of action, there have been a number of efforts to develop PLCB4 FabI inhibitors [14], particularly the enzyme from (saFabI) [15], and currently two Phase I trials are in progress for the saFabI inhibitors developed by Affinium Pharmaceuticals Inc. [16-17] and Fab Pharma SA. Atuveciclib (BAY-1143572) In the present review we describe current attempts to develop potent inhibitors of InhA. Three classes of inhibitors are based on isoniazid, the diazaborines and triclosan, antibacterial brokers that were subsequently shown to inhibit InhA. In addition we also summarize inhibitor discovery resulting from compounds recognized by high-throughput screening (HTS) that includes the pyrrolidine carboxamides, piperazine indoleformamides, pyrazoles and arylamides, and conclude with attempts to use fatty acids to inhibit InhA. Despite the structural diversity in the different InhA inhibitor classes, two generalizations arise from an analysis of the data. Firstly, in almost every case the inhibitors bind to the enzyme in the presence of the oxidized and/or reduced cofactor, albeit in the case of isoniazid and the diazaborines as covalent adducts of the cofactor [14]. And second of all, high affinity inhibition is usually often coupled to ordering of the substrate binding loop that is located close to the active site [14]. Given the importance of loop ordering and its relationship to the residence time of the inhibitor around the enzyme [18-19], we first briefly summarize the structural and mechanistic basis for high affinity inhibition of InhA and the FabI class of enoyl-ACP reductases. Structural and Mechanistic Basis for High Affinity Inhibition of Enoyl-ACP Reductases A central theme in FabI inhibitor discovery concerns the role that inhibitor binding plays in ordering of a loop of amino acids close to the active site. This sequence of amino acids is known as the substrate binding loop, and the importance of loop ordering during FabI inhibition was first noted in studies around the inhibition of the FabI by the diazaborine class of compounds [20]. Since then, X-ray crystallography has revealed ordered loops in a number of FabI:inhibitor complexes and those relevant to InhA are explained in this.