A Small Molecule Discrimination Map of the Antibiotic Resistance Kinome

SummaryKinase-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.

Graphical AbstractProtein kinase inhibitors can block the activity of antibiotic resistance kinases in vitro and in vivo.Figure optionsDownload full-size imageDownload high-quality image (677 K)Download as PowerPoint slideHighlights► Screens of 80 kinase inhibitors against 14 resistance kinases were performed ► These identified both broad and narrow spectrum inhibitors of resistance kinases ► 3D structure of the antibiotic kinase APH(2″)-IVa with quercetin and kanamycin ► Inhibitors demonstrated modest in vivo action against the resistance enzymes