In vivo validation of thymidylate kinase (TMK) with a rationally designed, selective antibacterial compound.
ACS Chem Biol
; 7(11): 1866-72, 2012 Nov 16.
Article
en En
| MEDLINE
| ID: mdl-22908966
ABSTRACT
There is an urgent need for new antibacterials that pinpoint novel targets and thereby avoid existing resistance mechanisms. We have created novel synthetic antibacterials through structure-based drug design that specifically target bacterial thymidylate kinase (TMK), a nucleotide kinase essential in the DNA synthesis pathway. A high-resolution structure shows compound TK-666 binding partly in the thymidine monophosphate substrate site, but also forming new induced-fit interactions that give picomolar affinity. TK-666 has potent, broad-spectrum Gram-positive microbiological activity (including activity against methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus), bactericidal action with rapid killing kinetics, excellent target selectivity over the human ortholog, and low resistance rates. We demonstrate in vivo efficacy against S. aureus in a murine infected-thigh model. This work presents the first validation of TMK as a compelling antibacterial target and provides a rationale for pursuing novel clinical candidates for treating Gram-positive infections through TMK.
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Nucleósido-Fosfato Quinasa
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Bacterias Grampositivas
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Antibacterianos
Límite:
Humans
Idioma:
En
Año:
2012
Tipo del documento:
Article