Please use this identifier to cite or link to this item: https://doi.org/10.1128/AAC.01571-17
Title: Whole-cell screen of fragment library identifies gut microbiota metabolite indole propionic acid as antitubercular
Authors: Negatu, D.A
Liu, J.J.J
Zimmerman, M
Kaya, F
Dartois, V
Aldrich, C.C
Gengenbacher, M 
Dicka, T 
Keywords: 2 (2,2,4,7 tetramethyl 1,2,3,4 tetrahydroquinolin 1 yl)ethan 1 ol hydrate
2 (3 chlorophenoxy)ethanethioamide
2 methyl 1h imidazole 4 carbothioamide
2 methyl 1h indol 5 amine
2,5 dimethyl 1 (2 thienylmethyl) 1 pyrrole 3 carboxylic acid
3 (4 fuorophenyl) 5 (methylsulfanyl) 1h pyrazole
4 (4 chlorophenoxy) 3,5 dimethyl 1 pyrazole
5 (4 chlorophenyl) n,n,2 trimethyl 3 furamide
5 phenylthiophene 2 carboxylic acid
6 chloro 1 (1,4 diazepan 1 yl) 1,3 benzothiazole
6 methyl 4 piperazino 2 (trifluoromethyl)quinoline
6,7,8,9 tetrahydrodibenzo[b,d]furan 2 amine
7 hydroxy 4 (trifluoromethyl) 2h chromen 2 one
beta carboline
carboxymethylcellulose
dimethyl sulfoxide
ethambutol
ethyl 2 amino 5 methyl 4 phenylthiophene 3 carboxylate
indolepropionic acid
isoniazid
isoquinoline 3 carboxylic acid
macrogol 400
methyl 3 hydroxy 1 benzothiophene 2 carboxylate
methyl isoquinoline 3 carboxylate
pyrazinamide
rifampicin
tuberculostatic agent
unclassified drug
unindexed drug
[2,2 bithiophene] 5 carboxylic acid
[6 (piperidin 1 yl)pyridin 2 yl]methanamine
propionic acid
propionic acid derivative
pyrazinamide
tuberculostatic agent
acute toxicity
animal experiment
animal model
animal tissue
antibacterial activity
antitubercular activity
area under the curve
Article
AUC (0-24 h)
bacterial load
bactericidal activity
CC50
chemotherapy
controlled study
cytotoxicity
drug bioavailability
drug blood level
drug delivery system
drug determination
drug efficacy
drug half life
drug mechanism
drug potency
drug screening
drug tolerability
elimination rate constant
erythrocyte
Escherichia coli
female
growth inhibition
HC50
hemolysis
Hep-G2 cell line
human
human cell
hydrogen bond
in vitro study
in vivo study
intestine flora
limit of quantitation
lung tuberculosis
maximum concentration
MIC50
MIC90
molecular library
molecule
monotherapy
mouse
Mycobacterium abscessus
Mycobacterium smegmatis
Mycobacterium tuberculosis
nonhuman
partition coefficient
plasma concentration-time curve
priority journal
selectivity index
single drug dose
splenic tuberculosis
Staphylococcus aureus
THP-1 cell line
whole cell
animal
Bagg albino mouse
drug effect
microbial sensitivity test
Animals
Antitubercular Agents
Female
Gastrointestinal Microbiome
Mice
Mice, Inbred BALB C
Microbial Sensitivity Tests
Mycobacterium tuberculosis
Propionates
Pyrazinamide
Issue Date: 2018
Publisher: American Society for Microbiology
Citation: Negatu, D.A, Liu, J.J.J, Zimmerman, M, Kaya, F, Dartois, V, Aldrich, C.C, Gengenbacher, M, Dicka, T (2018). Whole-cell screen of fragment library identifies gut microbiota metabolite indole propionic acid as antitubercular. Antimicrobial Agents and Chemotherapy 62 (3) : e01571-17. ScholarBank@NUS Repository. https://doi.org/10.1128/AAC.01571-17
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. Copyright © 2018 Negatu et al. This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license.
Source Title: Antimicrobial Agents and Chemotherapy
URI: https://scholarbank.nus.edu.sg/handle/10635/175122
ISSN: 0066-4804
DOI: 10.1128/AAC.01571-17
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