1. In vivo validation of thymidylate kinase (TMK) with a rationally designed, selective antibacterial compound
- Author
-
Peter Doig, Sameer Kawatkar, P. Ann Boriack-Sjodin, James T. Loch, Linda G. Otterson, Amy Kutschke, Selvi Pradeepan, Gabriel Martínez-Botella, Nelson B. Olivier, Joseph V. Newman, Satenig Guler, Oluyinka Green, Jacques Dumas, Andrew R. McKenzie, Eric Gangl, John Breen, Swati Prasad, Beth Andrews, Martin F. Hentemann, Diane Joseph-McCarthy, and Thomas A. Keating
- Subjects
Models, Molecular ,Staphylococcus aureus ,medicine.drug_class ,Antibiotics ,Biology ,medicine.disease_cause ,Gram-Positive Bacteria ,Biochemistry ,Thymidylate kinase ,chemistry.chemical_compound ,In vivo ,medicine ,Humans ,Nucleotide ,Gram-Positive Bacterial Infections ,chemistry.chemical_classification ,Thymidine monophosphate ,DNA synthesis ,Kinase ,General Medicine ,Staphylococcal Infections ,Anti-Bacterial Agents ,chemistry ,Molecular Medicine ,Nucleoside-Phosphate Kinase ,Enterococcus - 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.
- Published
- 2012