Resistance of Mycobacterium tuberculosis to indole 4-carboxamides occurs through alterations in drug metabolism and tryptophan biosynthesis

M. Daben J Libardo; Caroline J. Duncombe; Simon R. Green; Paul G. Wyatt; Stephen Thompson; Peter C. Ray; Thomas R. Ioerger; Sangmi Oh; Michael B. Goodwin; Helena I. M. Boshoff; Clifton E. Barry III

doi:10.1016/j.chembiol.2021.02.023

Resistance of Mycobacterium tuberculosis to indole 4-carboxamides occurs through alterations in drug metabolism and tryptophan biosynthesis

M. Daben J Libardo, Caroline J. Duncombe, Simon R. Green, Paul G. Wyatt, Stephen Thompson, Peter C. Ray, Thomas R. Ioerger, Sangmi Oh, Michael B. Goodwin, Helena I. M. Boshoff, Clifton E. Barry III (Lead / Corresponding author)

Drug Discovery Unit

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Abstract

Tryptophan biosynthesis represents an important potential drug target for new anti-TB drugs. We identified a series of indole-4-carboxamides with potent antitubercular activity. In vitro, Mycobacterium tuberculosis (Mtb) acquired resistance to these compounds through three discrete mechanisms: (1) a decrease in drug metabolism via loss-of-function mutations in the amidase that hydrolyses these carboxamides, (2) an increased biosynthetic rate of tryptophan precursors via loss of allosteric feedback inhibition of anthranilate synthase (TrpE), and (3) mutation of tryptophan synthase (TrpAB) that decreased incorporation of 4-aminoindole into 4-aminotryptophan. Thus, these indole-4-carboxamides act as prodrugs of a tryptophan antimetabolite, 4-aminoindole.

Original language	English
Pages (from-to)	1180-1191.e20
Number of pages	32
Journal	Cell Chemical Biology
Volume	28
Issue number	8
Early online date	13 Mar 2021
DOIs	https://doi.org/10.1016/j.chembiol.2021.02.023
Publication status	Published - 19 Aug 2021

Keywords

tuberculosis
drug mechanism of action
pro-drug
tryptophan metabolism
antimetabolite

ASJC Scopus subject areas

Drug Discovery
Molecular Medicine
Molecular Biology
Biochemistry
Clinical Biochemistry
Pharmacology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.chembiol.2021.02.023Licence: CC BY

Final Published VersionFinal published version, 4.27 MBLicence: CC BY

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Libardo, M. D. J., Duncombe, C. J., Green, S. R., Wyatt, P. G., Thompson, S., Ray, P. C., Ioerger, T. R., Oh, S., Goodwin, M. B., Boshoff, H. I. M., & Barry III, C. E. (2021). Resistance of Mycobacterium tuberculosis to indole 4-carboxamides occurs through alterations in drug metabolism and tryptophan biosynthesis. Cell Chemical Biology, 28(8), 1180-1191.e20. https://doi.org/10.1016/j.chembiol.2021.02.023

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title = "Resistance of Mycobacterium tuberculosis to indole 4-carboxamides occurs through alterations in drug metabolism and tryptophan biosynthesis",

abstract = "Tryptophan biosynthesis represents an important potential drug target for new anti-TB drugs. We identified a series of indole-4-carboxamides with potent antitubercular activity. In vitro, Mycobacterium tuberculosis (Mtb) acquired resistance to these compounds through three discrete mechanisms: (1) a decrease in drug metabolism via loss-of-function mutations in the amidase that hydrolyses these carboxamides, (2) an increased biosynthetic rate of tryptophan precursors via loss of allosteric feedback inhibition of anthranilate synthase (TrpE), and (3) mutation of tryptophan synthase (TrpAB) that decreased incorporation of 4-aminoindole into 4-aminotryptophan. Thus, these indole-4-carboxamides act as prodrugs of a tryptophan antimetabolite, 4-aminoindole.",

keywords = "tuberculosis, drug mechanism of action, pro-drug, tryptophan metabolism, antimetabolite",

author = "Libardo, {M. Daben J} and Duncombe, {Caroline J.} and Green, {Simon R.} and Wyatt, {Paul G.} and Stephen Thompson and Ray, {Peter C.} and Ioerger, {Thomas R.} and Sangmi Oh and Goodwin, {Michael B.} and Boshoff, {Helena I. M.} and {Barry III}, {Clifton E.}",

note = "This work was funded (in part) by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases , NIH, and (in part) by funding from the Bill and Melinda Gates Foundation.",

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Libardo, MDJ, Duncombe, CJ, Green, SR, Wyatt, PG, Thompson, S, Ray, PC, Ioerger, TR, Oh, S, Goodwin, MB, Boshoff, HIM & Barry III, CE 2021, 'Resistance of Mycobacterium tuberculosis to indole 4-carboxamides occurs through alterations in drug metabolism and tryptophan biosynthesis', Cell Chemical Biology, vol. 28, no. 8, pp. 1180-1191.e20. https://doi.org/10.1016/j.chembiol.2021.02.023

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T1 - Resistance of Mycobacterium tuberculosis to indole 4-carboxamides occurs through alterations in drug metabolism and tryptophan biosynthesis

AU - Libardo, M. Daben J

AU - Duncombe, Caroline J.

AU - Green, Simon R.

AU - Wyatt, Paul G.

AU - Thompson, Stephen

AU - Ray, Peter C.

AU - Ioerger, Thomas R.

AU - Oh, Sangmi

AU - Goodwin, Michael B.

AU - Boshoff, Helena I. M.

AU - Barry III, Clifton E.

N1 - This work was funded (in part) by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases , NIH, and (in part) by funding from the Bill and Melinda Gates Foundation.

PY - 2021/8/19

Y1 - 2021/8/19

N2 - Tryptophan biosynthesis represents an important potential drug target for new anti-TB drugs. We identified a series of indole-4-carboxamides with potent antitubercular activity. In vitro, Mycobacterium tuberculosis (Mtb) acquired resistance to these compounds through three discrete mechanisms: (1) a decrease in drug metabolism via loss-of-function mutations in the amidase that hydrolyses these carboxamides, (2) an increased biosynthetic rate of tryptophan precursors via loss of allosteric feedback inhibition of anthranilate synthase (TrpE), and (3) mutation of tryptophan synthase (TrpAB) that decreased incorporation of 4-aminoindole into 4-aminotryptophan. Thus, these indole-4-carboxamides act as prodrugs of a tryptophan antimetabolite, 4-aminoindole.

AB - Tryptophan biosynthesis represents an important potential drug target for new anti-TB drugs. We identified a series of indole-4-carboxamides with potent antitubercular activity. In vitro, Mycobacterium tuberculosis (Mtb) acquired resistance to these compounds through three discrete mechanisms: (1) a decrease in drug metabolism via loss-of-function mutations in the amidase that hydrolyses these carboxamides, (2) an increased biosynthetic rate of tryptophan precursors via loss of allosteric feedback inhibition of anthranilate synthase (TrpE), and (3) mutation of tryptophan synthase (TrpAB) that decreased incorporation of 4-aminoindole into 4-aminotryptophan. Thus, these indole-4-carboxamides act as prodrugs of a tryptophan antimetabolite, 4-aminoindole.

KW - tuberculosis

KW - drug mechanism of action

KW - pro-drug

KW - tryptophan metabolism

KW - antimetabolite

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SN - 2451-9448

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SP - 1180-1191.e20

JO - Cell Chemical Biology

JF - Cell Chemical Biology

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Resistance of Mycobacterium tuberculosis to indole 4-carboxamides occurs through alterations in drug metabolism and tryptophan biosynthesis

Abstract

Keywords

ASJC Scopus subject areas

UN SDGs

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