Antibiotics. Targeting DnaN for tuberculosis therapy using novel griselimycins.
Science
; 348(6239): 1106-12, 2015 Jun 05.
Article
en En
| MEDLINE
| ID: mdl-26045430
ABSTRACT
The discovery of Streptomyces-produced streptomycin founded the age of tuberculosis therapy. Despite the subsequent development of a curative regimen for this disease, tuberculosis remains a worldwide problem, and the emergence of multidrug-resistant Mycobacterium tuberculosis has prioritized the need for new drugs. Here we show that new optimized derivatives from Streptomyces-derived griselimycin are highly active against M. tuberculosis, both in vitro and in vivo, by inhibiting the DNA polymerase sliding clamp DnaN. We discovered that resistance to griselimycins, occurring at very low frequency, is associated with amplification of a chromosomal segment containing dnaN, as well as the ori site. Our results demonstrate that griselimycins have high translational potential for tuberculosis treatment, validate DnaN as an antimicrobial target, and capture the process of antibiotic pressure-induced gene amplification.
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Péptidos Cíclicos
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Proteínas Bacterianas
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Tuberculosis Resistente a Múltiples Medicamentos
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Terapia Molecular Dirigida
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Mycobacterium tuberculosis
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Antituberculosos
Límite:
Animals
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Humans
Idioma:
En
Revista:
Science
Año:
2015
Tipo del documento:
Article