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)

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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 languageEnglish
Pages (from-to)1–12.e1–e20
Number of pages32
JournalCell Chemical Biology
Volume28
Early online date13 Mar 2021
DOIs
Publication statusE-pub ahead of print - 13 Mar 2021

Keywords

  • tuberculosis
  • drug mechanism of action
  • pro-drug
  • tryptophan metabolism
  • antimetabolite

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