Repurposed kinase inhibitors and β-lactams as a novel therapy for antibiotic resistant bacteria

Abstract

Antibiotic resistant bacteria are an increasing global problem, and pathogenic actinomycetes and firmicutes are particularly challenging obstacles. These pathogens share several eukaryotic-like kinases that present antibiotic development opportunities. We used computational modelling to identify human kinase inhibitors that could be repurposed towards bacteria as part of a novel combination therapy. The computational model suggested a family of inhibitors, the imidazopyridine aminofurazans (IPAs), bind PknB with high affinity. We found that these inhibitors biochemically inhibit PknB, with potency roughly following the predicted models. A novel x-ray structure confirmed that the inhibitors bind as predicted and made favorable protein contacts with the target. These inhibitors also have antimicrobial activity towards Mycobacteria and Nocardia, and normally ineffective {beta}-lactams can potentiate IPAs to more efficiently inhibit growth of these pathogens. Collectively, our data show that in silico modeling can be used as a tool to discover promising drug leads, and the inhibitors we discovered can synergize with clinically relevant antibiotics to restore their efficacy against bacteria with limited treatment options.