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 | |
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