Whole-cell screen of fragment library identifies gut microbiota metabolite indole propionic acid as antitubercular

Dereje A. Negatu, Joe J.J. Liu, Matthew Zimmerman, Firat Kaya, Véronique Dartois, Courtney C. Aldrich, Martin Gengenbacher, Thomas Dicka

Research output: Contribution to journalArticlepeer-review

19 Scopus citations

Abstract

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.

Original languageEnglish (US)
Article numbere01571-17
JournalAntimicrobial agents and chemotherapy
Volume62
Issue number3
DOIs
StatePublished - Mar 2018

Bibliographical note

Funding 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.

Publisher Copyright:
Copyright © 2018 Negatu et al. This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license.

Keywords

  • Fragments
  • Gut microbiota
  • Indole propionic acid
  • Tuberculosis

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