Journal
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY
Volume 62, Issue 3, Pages -Publisher
AMER SOC MICROBIOLOGY
DOI: 10.1128/AAC.01571-17
Keywords
tuberculosis; fragments; indole propionic acid; gut microbiota
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Funding
- Singapore Ministry of Health's National Medical Research Council under TCR Flagship grant [NMRC/TCR/011-NUHS/2014]
- Singapore Ministry of Health's National Medical Research Council under Center Grant MINE Core [4 BSL-3 NMRC/CG/013/2013]
- Singapore International Graduate Award scholarship [SING-2014-2-0626]
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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.
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