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Antibiotics

I want a new drug

Proc. Natl. Acad. Sci. USA http://dx.doi.org/10.1073/pnas.1600630113 (2016)

Credit: PNAS

Although tuberculosis is one of the leading infectious causes of mortality and morbidity in the world, reports of drugs that kill its causative bacterium, Mycobacterium tuberculosis, through a new mechanism of action are very rare. Kasbekar et al. used a fluorescence-based assay to screen a library of 479,984 small molecules for inhibitors of fumarate hydratase, an essential enzyme in the tricarboxylic acid cycle. M. tuberculosis and human fumarate hydratase are highly homologous, with an overall sequence identity of 53% and identical amino acid residues in their active sites, so it has been very difficult to find selective inhibitors of M. tuberculosis fumarate hydratase. The authors identified two structurally similar molecules that were potent inhibitors of the bacterial enzyme in vitro, and comparison of the X-ray crystal structures of the enzyme in the absence and presence of one of the inhibitors revealed that two molecules of the compound bind in the same allosteric pocket. The small molecule did not inhibit the human enzyme in vitro, which the authors believe is because the amino acids in the allosteric sites of the two homologs are quite different. Although the molecule inhibited the growth of M. tuberculosis under aerobic conditions, the authors believe that significant optimization is still required before they will have an advanced probe for future studies.

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Finkelstein, J. I want a new drug. Nat Chem Biol 12, 575 (2016). https://doi.org/10.1038/nchembio.2137

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