VanX is an induced zinc metallo d-Ala-d-Ala dipeptidase involved in the viable remodeling of bacterial cell wall that is essential for the development of VREF. Here we report two cyclic thiohydroxamic acid-based peptide analogs that were designed, synthesized and investigated as vancomycin re-sensitizing agents. These compounds exhibit low micromolar inhibitory activity against vanX, with low cytotoxicity and were shown to increase vancomycin sensitivity against VREF. The improved pharmacological properties of these novel inhibitors over previous transition state mimics should provide an enhanced platform for designing potent vanX inhibitors for overcoming vancomycin resistance.
Bibliographical noteFunding Information:
We thank Prof. Christopher Walsh for providing the plasmid used in the expression of vanX. This research was supported by the faculty development grant from the University of Minnesota Academic Health Center . We thank the University of Minnesota Supercomputing Institute and the Center for Drug Design for providing the necessary computational and instrumentation resources. We thank Dr. Fred Schendel, Biotechnology Institute, University of Minnesota for vanX protein preparation. We also thank Jesse Meyer for performing the biochemical assays.
- Drug resistance
- Thiohydroxamic acid