Beta-ketoacyl-(acyl-carrier-protein) Synthase III - Inhibitors

Inhibitors

At least two of the existing drugs for tuberculosis were originally derived from microbes; cerulenin from the fungus Cephalosporium caerulens and thiolactomycin (TLM) from the actinomycete Nocardia spp. Isoniazid (isonicotinic acid hydrazide), ethionamide, triclosan and TLM are known to specifically inhibit mycolic acid biosynthesis. Derivatives of TLM and related compounds are being screened to improve efficacy.

While much has been learned from these structural studies and rational design is an excellent approach to develop novel inhibitors, alternative approaches such as bio-prospecting may reveal unexpected compounds such as an allosteric inhibitor discovered by Daines et al.. This could be especially important given that phosphorylation of mycolate synthesis enzymes is suggested to be critical to regulation and kinase domains are known to have multiple control mechanisms remote from ligand binding and active sites.

Following the discovery that phomallenic acids isolated from a leaf litter fungus identified as Phoma sp. are inhibitors of the FabH/FabF. Wang et al. recently reported their discovery from the soil bacterium Streptomyces platensis of a novel natural inhibitor of FabH with in vivo activity called platencin. These were found by screening 250,000 extracts of soil bacteria and fungi, demonstrating the viability of bio-prospecting. While a potentially useful antibiotic in its own right, it has now been shown that platensimycin is not specifically active on mtFabH.

It is speculated that novel inhibitors will most likely be small molecules of relatively low polarity considering the catalytic sites of the mtFabH homodimer are hidden in relatively hydrophobic pockets and the need to traverse capsules of established bacilli. This is supported by the poor water solubility of an inhibitor to ecFabH. It is also hoped that by being small molecules, their synthesis or biosynthesis will be simple and cheap, thereby enhancing affordability of subsequent drugs to developing countries. Techniques for screening efficacy of inhibitors are available.