Resistance of Mycobacterium tuberculosis to indole 4-carboxamides occurs through alterations in drug metabolism and tryptophan biosynthesis.
Cell Chem Biol
; 28(8): 1180-1191.e20, 2021 08 19.
Article
em En
| MEDLINE
| ID: mdl-33765439
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.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Triptofano
/
Farmacorresistência Bacteriana
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Indóis
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Mycobacterium tuberculosis
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Antituberculosos
Limite:
Animals
Idioma:
En
Revista:
Cell Chem Biol
Ano de publicação:
2021
Tipo de documento:
Article
País de afiliação:
Estados Unidos