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DA Negatu, JJJ Liu, M Zimmerman, F Kaya, V Dartois, CC Aldrich, M Gengenbacher and T Dick
Abstract
Several key tuberculosis drugs including pyrazinamide, with a molecular weight of 123.1 g/mol, are smaller than the usual drug like molecules. Current drug discovery efforts focus on the screening of larger compounds with molecular weights centered around 400-500 g/mol. Fragment (molecular weight < 300 g/mol) libraries have not been systematically explored for antitubercular activity. Here we screened a collection of 1000 fragments, present in the Maybridge Ro3 library, for whole cell activity against Mycobacterium tuberculosis Twenty-nine primary hits showed dose-dependent growth inhibition equal or better than pyrazinamide. The most potent hit, indole propionic acid (IPA, 3-(1H-indol-3-yl)propanoic acid), a metabolite produced by the gut microbiota, was profiled in vivo The molecule was well tolerated in mice and showed adequate pharmacokinetic properties. In an acute mouse model of tuberculosis infection, IPA reduced the bacterial load in the spleen 7 fold. Our results suggest that IPA should be evaluated as an add-on to current regimens and that fragment libraries should be further explored to identify antimycobacterial lead candidates.
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Concepts
Oxygen, Pharmacology, Gut flora, Butyric acid, Molecular mass, Bacteria, Molecule, Tuberculosis
MeSH headings
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