Beta-ketoacyl-ACP synthase III

β-Ketoacyl-acyl-carrier-protein synthase III is involved in the dissociated (or type II) fatty-acid biosynthesis system that occurs in plants and bacteria.

Crystal structures of FabH have been reported from Mycobacterium tuberculosis,[1][8][9] Staphylococcus aureus,[10] Escherichia coli,[11] and Thermus thermophilus.

Inhibition strategies based on rational design could include competitive displacement of the substrates or disruption of the catalytic site.

[19] 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.

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.

[25][26] 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.

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.

[31][32] Despite the availability of the BCG vaccine and multiple antibiotics, until 2005 TB resurged due to multidrug resistance, exacerbated by incubation in immune-compromised AIDS victims, drug treatment non-compliance, and ongoing systemic deficiencies of healthcare in developing countries.

Inhibitors against mtFabH, or against other enzymes of the FAS-II pathway, may have broader utility, such as the treatment of multidrug-resistant Staphylococcus aureus, and Plasmodium falciparum, the causative agent of another serious refractory problem, malaria.