Journal
ACS CHEMICAL BIOLOGY
Volume 7, Issue 11, Pages 1866-1872Publisher
AMER CHEMICAL SOC
DOI: 10.1021/cb300316n
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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 wink 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.
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