Avoiding Antibiotic Inactivation in Mycobacterium tuberculosis by Rv3406 through Strategic Nucleoside Modification.
ACS Infect Dis
; 4(7): 1102-1113, 2018 07 13.
Article
em En
| MEDLINE
| ID: mdl-29663798
ABSTRACT
5'-[ N-(d-biotinoyl)sulfamoyl]amino-5'-deoxyadenosine (Bio-AMS, 1) possesses selective activity against Mycobacterium tuberculosis ( Mtb) and arrests fatty acid and lipid biosynthesis through inhibition of the Mycobacterium tuberculosis biotin protein ligase ( MtBPL). Mtb develops spontaneous resistance to 1 with a frequency of at least 1 × 10-7 by overexpression of Rv3406, a type II sulfatase that enzymatically inactivates 1. In an effort to circumvent this resistance mechanism, we describe herein strategic modification of the nucleoside at the 5'-position to prevent enzymatic inactivation. The new analogues retained subnanomolar potency to MtBPL ( KD = 0.66-0.97 nM), and 5' R- C-methyl derivative 6 exhibited identical antimycobacterial activity toward Mtb H37Rv, MtBPL overexpression, and an isogenic Rv3406 overexpression strain (minimum inhibitory concentration, MIC = 1.56 µM). Moreover, 6 was not metabolized by recombinant Rv3406 and resistant mutants to 6 could not be isolated (frequency of resistance <1.4 × 10-10) demonstrating it successfully overcame Rv3406-mediated resistance.
Palavras-chave
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Carbono-Nitrogênio Ligases
/
Farmacorresistência Bacteriana
/
Mycobacterium tuberculosis
/
Nucleosídeos
/
Antituberculosos
Idioma:
En
Ano de publicação:
2018
Tipo de documento:
Article