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

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. Invitro, 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.

published proceedings

  • Cell Chem Biol

altmetric score

  • 6.7

author list (cited authors)

  • Libardo, M., Duncombe, C. J., Green, S. R., Wyatt, P. G., Thompson, S., Ray, P. C., ... Barry, C. E.

citation count

  • 4

complete list of authors

  • Libardo, M Daben J||Duncombe, Caroline J||Green, Simon R||Wyatt, Paul G||Thompson, Stephen||Ray, Peter C||Ioerger, Thomas R||Oh, Sangmi||Goodwin, Michael B||Boshoff, Helena IM||Barry, Clifton E

publication date

  • August 2021