Several key antituberculosis drugs, including pyrazinamide, with a molecular mass 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 masses centered around 400 to 500 g/mol. Fragment (molecular mass 300 g/mol) libraries have not been systematically explored for antitubercular activity. Here we screened a collection of 1,000 fragments, present in the Maybridge Ro3 library, for whole-cell activity against Mycobacterium tuberculosis. Twenty-nine primary hits showed dose-dependent growth inhibition equal to or better than that of 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 a mouse model of acute M. 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.
Bibliographical noteFunding Information:
This research was supported by the Singapore Ministry of Health’s National Medical Research Council under TCR Flagship grant NMRC/TCR/011-NUHS/2014 and Center Grant MINE Core number 4 BSL-3 NMRC/CG/013/2013 to T.D. and is part of the Singapore Programme of Research Investigating New Approaches to Treatment of Tuberculosis (SPRINT-TB; http://www.sprinttb.org), led by Nick Paton and managed by Pauline Yoong. D.A.N. was supported by Singapore International Graduate Award scholarship SING-2014-2-0626.
Copyright © 2018 Negatu et al. This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license.
- Gut microbiota
- Indole propionic acid