A small molecule discrimination map of the antibiotic resistance kinome |
| |
| Authors: | Shakya Tushar Stogios Peter J Waglechner Nicholas Evdokimova Elena Ejim Linda Blanchard Jan E McArthur Andrew G Savchenko Alexei Wright Gerard D |
| |
| Affiliation: | 1M.G. DeGroote Institute for Infectious Disease Research, Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON, L8S 3Z5, Canada;2Department of Chemical Engineering and Applied Chemistry, University of Toronto, Toronto, ON, M5G 1L6, Canada;3Center for Structural Genomics of Infectious Diseases (CSGID), Toronto, ON, M5G 1L6;4High-Throughput Screening Lab, Centre for Microbial Chemical Biology, McMaster University, Hamilton, ON, L8S 3Z5, Canada;5Andrew McArthur Consulting, Hamilton, ON L8S 3P6, Canada |
| |
| Abstract: | Kinase-mediated resistance to antibiotics is a significant clinical challenge. These enzymes share a common protein fold characteristic of Ser/Thr/Tyr protein kinases. We screened 14 antibiotic resistance kinases against 80 chemically diverse protein kinase inhibitors to map resistance kinase chemical space. The screens identified molecules with both broad and narrow inhibition profiles, proving that protein kinase inhibitors offer privileged chemical matter with the potential to block antibiotic resistance. One example is the flavonol quercetin, which inhibited a number of resistance kinases in vitro and in vivo. This activity was rationalized by determination of the crystal structure of the aminoglycoside kinase APH(2″)-IVa in complex with quercetin and its antibiotic substrate kanamycin. Our data demonstrate that protein kinase inhibitors offer chemical scaffolds that can block antibiotic resistance, providing leads for co-drug design. |
| |
| Keywords: | |
| 本文献已被 ScienceDirect PubMed 等数据库收录！ |
|
