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

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

Author information

1
Antibacterial Drug Discovery Laboratory, Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
2
Tuberculosis Research Laboratory, Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
3
St. Peter TB Specialized Hospital, Addis Ababa, Ethiopia.
4
Public Health Research Institute, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, New Jersey, USA.
5
Department of Medicinal Chemistry, College of Pharmacy, University of Minnesota, Minneapolis, Minnesota, USA.
6
Tuberculosis Research Laboratory, Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore mg1435@njms.rutgers.edu td367@njms.rutgers.edu.
7
Antibacterial Drug Discovery Laboratory, Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore mg1435@njms.rutgers.edu td367@njms.rutgers.edu.

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.

KEYWORDS:

fragments; gut microbiota; indole propionic acid; tuberculosis

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