Inhibitors of Fabl, an enzyme drug target in the bacterial fatty acid biosynthesis pathway

The modem age of drug discovery, which had been slowly gathering momentum during the early part of the twentieth century, exploded into life in the 1940s with the isolation of penicillin and streptomycin. The immense success of these early drug discovery efforts prompted the general view that many infectious diseases would now be effectively controlled and even eradicated. However this initial optimism was misplaced, and pathogens such as multidrug-resistant Mycobacterium tuberculosis and methicillin-resistant Staphylococcus aureus present a major current threat to human health. Drug resistance arises through the unrelenting pressure of natural selection, and there is thus a continuing need to identify novel drug targets and develop chemotherapeutics that circumvent existing drug resistance mechanisms. In this Account we summarize current progress in developing inhibitors of Fabl, the NADH-dependent enoyl reductase from the type II bacterial fatty add biosynthesis pathway (FAS-II), a validated but currently underexploited target for drug discovery. The Fabl inhibitors have been divided into two groups, based on whether they form a covalent adduct with the NAD(+) cofactor. Inhibitors that form a covalent adduct include the diazaborines, as well as the front-line tuberculosis drug isoniazid. The NAD adducts formed with these compounds are formally bisubstrate enzyme inhibitors, and we summarize progress in developing novel leads based on these pharmacophores. Inhibitors that do not form covalent adducts form a much larger group, although generally these compounds also require the cofactor to be bound to the enzyme. Using structure-based approaches, we have developed a series of alkyl diphenyl ethers that are nanomolar inhibitors of InhA, the Fabl from M. tuberculosis, and that are active against INH-resistant strains of M. tuberculosis. This rational approach to inhibitor development is based on the proposal that high-affinity inhibition of the Fabl enzymes is coupled to the ordering of a loop of amino adds dose to the active site. Compounds that promote loop ordering are slow onset Fabl inhibitors with increased residence time on the enzyme. The diphenyl ether skeleton has also been used as a framework by us and others to develop potent inhibitors of the Fabl enzymes from other pathogens such as Escherichia coli, S. aureus; and Plasmodium falciparum. Meanwhile chemical optimization of compounds identified in high-throughput screening programs has resulted in the identification of several classes of heteroaromatic Fabl inhibitors with potent activity both in intro and in vivo. Finally, screening of natural product libraries may provide useful chemical entities for the development of novel agents with low toxicity. While the discovery that not all pathogens contain Fabl homologues has led to reduced industrial interest in Fabl as a broad spectrum target, there is substantial optimism that Fabl inhibitors can be developed for disease-specific applications. In addition, the availability of genome sequencing data, improved methods for target identification and validation, and the development of novel approaches for determining the mode of action of current drugs will all play critical roles in the road ahead and in exploiting other components of the FAS-II pathway.