title: A small molecule discrimination map of the antibiotic resistance kinome.
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.
authors.affiliation: M.G. DeGroote Institute for Infectious Disease Research, Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON, L8S 3Z5, Canada.
authors.forename: Tushar
authors.initials: T
authors.lastname: Shakya
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Stogios
authors.forename: Nicholas
authors.initials: N
authors.lastname: Waglechner
authors.forename: Elena
authors.initials: E
authors.lastname: Evdokimova
authors.forename: Linda
authors.initials: L
authors.lastname: Ejim
authors.forename: Jan E
authors.initials: JE
authors.lastname: Blanchard
authors.forename: Andrew G
authors.initials: AG
authors.lastname: McArthur
authors.forename: Alexei
authors.initials: A
authors.lastname: Savchenko
authors.forename: Gerard D
authors.initials: GD
authors.lastname: Wright
mesh_terms: D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000494:pharmacology*; D001665:Binding Sites; D018360:Crystallography, X-Ray; D015195:Drug Design; D024881:Drug Resistance, Bacterial; D004789:Enzyme Activation / Q000187:drug effects; D007700:Kinetics; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000737:chemistry / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D011494:Protein Kinases / Q000737:chemistry* / Q000378:metabolism; D017434:Protein Structure, Tertiary; D011794:Quercetin / Q000737:chemistry / Q000494:pharmacology; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D000900:Anti-Bacterial Agents; D047428:Protein Kinase Inhibitors; D054852:Small Molecule Libraries; D011794:Quercetin; D011494:Protein Kinases; D017853:Phosphotransferases (Alcohol Group Acceptor); C048564:aminoglycoside 2''-phosphotransferase