Gut Microbiota Metabolite Indole Propionic Acid Targets Tryptophan Biosynthesis in <italic toggle="yes">Mycobacterium tuberculosis</italic>

ABSTRACT Indole propionic acid (IPA), produced by the gut microbiota, is active against Mycobacterium tuberculosis in vitro and in vivo. However, its mechanism of action is unknown. IPA is the deamination product of tryptophan (Trp) and thus a close structural analog of this essential aromatic amino...

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Autores principales:	Dereje Abate Negatu, Yoshiyuki Yamada, Yu Xi, Mei Lin Go, Matthew Zimmerman, Uday Ganapathy, Véronique Dartois, Martin Gengenbacher, Thomas Dick
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2019
Materias:	NTM TrpE allosteric inhibitor antibiotic tryptophan mimic Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/0e2fba6e963346fe96944f4609ebe797
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spelling	oai:doaj.org-article:0e2fba6e963346fe96944f4609ebe7972021-11-15T15:55:25ZGut Microbiota Metabolite Indole Propionic Acid Targets Tryptophan Biosynthesis in <italic toggle="yes">Mycobacterium tuberculosis</italic>10.1128/mBio.02781-182150-7511https://doaj.org/article/0e2fba6e963346fe96944f4609ebe7972019-04-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.02781-18https://doaj.org/toc/2150-7511ABSTRACT Indole propionic acid (IPA), produced by the gut microbiota, is active against Mycobacterium tuberculosis in vitro and in vivo. However, its mechanism of action is unknown. IPA is the deamination product of tryptophan (Trp) and thus a close structural analog of this essential aromatic amino acid. De novo Trp biosynthesis in M. tuberculosis is regulated through feedback inhibition: Trp acts as an allosteric inhibitor of anthranilate synthase TrpE, which catalyzes the first committed step in the Trp biosynthesis pathway. Hence, we hypothesized that IPA may mimic Trp as an allosteric inhibitor of TrpE and exert its antimicrobial effect by blocking synthesis of Trp at the TrpE catalytic step. To test our hypothesis, we carried out metabolic, chemical rescue, genetic, and biochemical analyses. Treatment of mycobacteria with IPA inhibited growth and reduced the intracellular level of Trp, an effect abrogated upon supplementation of Trp in the medium. Missense mutations at the allosteric Trp binding site of TrpE eliminated Trp inhibition and caused IPA resistance. In conclusion, we have shown that IPA blocks Trp biosynthesis in M. tuberculosis via inhibition of TrpE by mimicking the physiological allosteric inhibitor of this enzyme. IMPORTANCE New drugs against tuberculosis are urgently needed. The tryptophan (Trp) analog indole propionic acid (IPA) is the first antitubercular metabolite produced by human gut bacteria. Here, we show that this antibiotic blocks Trp synthesis, an in vivo essential biosynthetic pathway in M. tuberculosis. Intriguingly, IPA acts by decoupling a bacterial feedback regulatory mechanism: it mimics Trp as allosteric inhibitor of anthranilate synthase, thereby switching off Trp synthesis regardless of intracellular Trp levels. The identification of IPA’s target paves the way for the discovery of more potent TrpE ligands employing rational, target-based lead optimization.Dereje Abate NegatuYoshiyuki YamadaYu XiMei Lin GoMatthew ZimmermanUday GanapathyVéronique DartoisMartin GengenbacherThomas DickAmerican Society for MicrobiologyarticleNTMTrpEallosteric inhibitorantibiotictryptophan mimicMicrobiologyQR1-502ENmBio, Vol 10, Iss 2 (2019)
institution	DOAJ
collection	DOAJ
language	EN
topic	NTM TrpE allosteric inhibitor antibiotic tryptophan mimic Microbiology QR1-502
spellingShingle	NTM TrpE allosteric inhibitor antibiotic tryptophan mimic Microbiology QR1-502 Dereje Abate Negatu Yoshiyuki Yamada Yu Xi Mei Lin Go Matthew Zimmerman Uday Ganapathy Véronique Dartois Martin Gengenbacher Thomas Dick Gut Microbiota Metabolite Indole Propionic Acid Targets Tryptophan Biosynthesis in <italic toggle="yes">Mycobacterium tuberculosis</italic>
description	ABSTRACT Indole propionic acid (IPA), produced by the gut microbiota, is active against Mycobacterium tuberculosis in vitro and in vivo. However, its mechanism of action is unknown. IPA is the deamination product of tryptophan (Trp) and thus a close structural analog of this essential aromatic amino acid. De novo Trp biosynthesis in M. tuberculosis is regulated through feedback inhibition: Trp acts as an allosteric inhibitor of anthranilate synthase TrpE, which catalyzes the first committed step in the Trp biosynthesis pathway. Hence, we hypothesized that IPA may mimic Trp as an allosteric inhibitor of TrpE and exert its antimicrobial effect by blocking synthesis of Trp at the TrpE catalytic step. To test our hypothesis, we carried out metabolic, chemical rescue, genetic, and biochemical analyses. Treatment of mycobacteria with IPA inhibited growth and reduced the intracellular level of Trp, an effect abrogated upon supplementation of Trp in the medium. Missense mutations at the allosteric Trp binding site of TrpE eliminated Trp inhibition and caused IPA resistance. In conclusion, we have shown that IPA blocks Trp biosynthesis in M. tuberculosis via inhibition of TrpE by mimicking the physiological allosteric inhibitor of this enzyme. IMPORTANCE New drugs against tuberculosis are urgently needed. The tryptophan (Trp) analog indole propionic acid (IPA) is the first antitubercular metabolite produced by human gut bacteria. Here, we show that this antibiotic blocks Trp synthesis, an in vivo essential biosynthetic pathway in M. tuberculosis. Intriguingly, IPA acts by decoupling a bacterial feedback regulatory mechanism: it mimics Trp as allosteric inhibitor of anthranilate synthase, thereby switching off Trp synthesis regardless of intracellular Trp levels. The identification of IPA’s target paves the way for the discovery of more potent TrpE ligands employing rational, target-based lead optimization.
format	article
author	Dereje Abate Negatu Yoshiyuki Yamada Yu Xi Mei Lin Go Matthew Zimmerman Uday Ganapathy Véronique Dartois Martin Gengenbacher Thomas Dick
author_facet	Dereje Abate Negatu Yoshiyuki Yamada Yu Xi Mei Lin Go Matthew Zimmerman Uday Ganapathy Véronique Dartois Martin Gengenbacher Thomas Dick
author_sort	Dereje Abate Negatu
title	Gut Microbiota Metabolite Indole Propionic Acid Targets Tryptophan Biosynthesis in <italic toggle="yes">Mycobacterium tuberculosis</italic>
title_short	Gut Microbiota Metabolite Indole Propionic Acid Targets Tryptophan Biosynthesis in <italic toggle="yes">Mycobacterium tuberculosis</italic>
title_full	Gut Microbiota Metabolite Indole Propionic Acid Targets Tryptophan Biosynthesis in <italic toggle="yes">Mycobacterium tuberculosis</italic>
title_fullStr	Gut Microbiota Metabolite Indole Propionic Acid Targets Tryptophan Biosynthesis in <italic toggle="yes">Mycobacterium tuberculosis</italic>
title_full_unstemmed	Gut Microbiota Metabolite Indole Propionic Acid Targets Tryptophan Biosynthesis in <italic toggle="yes">Mycobacterium tuberculosis</italic>
title_sort	gut microbiota metabolite indole propionic acid targets tryptophan biosynthesis in <italic toggle="yes">mycobacterium tuberculosis</italic>
publisher	American Society for Microbiology
publishDate	2019
url	https://doaj.org/article/0e2fba6e963346fe96944f4609ebe797
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Gut Microbiota Metabolite Indole Propionic Acid Targets Tryptophan Biosynthesis in <italic toggle="yes">Mycobacterium tuberculosis</italic>

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