Whole-Cell Screen of Fragment Library Identifies Gut Microbiota Metabolite Indole Propionic Acid as Antitubercular

Antimicrob Agents Chemother. 2018 Feb 23;62(3):e01571-17. doi: 10.1128/AAC.01571-17. Print 2018 Mar.


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.

Keywords: fragments; gut microbiota; indole propionic acid; tuberculosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antitubercular Agents / pharmacology*
  • Female
  • Gastrointestinal Microbiome / drug effects*
  • Mice
  • Mice, Inbred BALB C
  • Microbial Sensitivity Tests
  • Mycobacterium tuberculosis / drug effects
  • Propionates / pharmacology*
  • Pyrazinamide / pharmacology


  • Antitubercular Agents
  • Propionates
  • Pyrazinamide
  • propionic acid