Repurposing Eukaryotic Kinase Inhibitors as Colistin Adjuvants in Gram-Negative Bacteria

Kinase inhibitors comprise a diverse
cohort of chemical scaffolds that are active in multiple biological
systems. Currently, thousands of eukaryotic kinase inhibitors are
commercially available, have well-characterized targets, and often
carry pharmaceutically favorable toxicity profiles. Recently, our
group disclosed that derivatives of the natural product meridianin
D, a known inhibitor of eukaryotic kinases, modulated behaviors of
both Gram-positive and Gram-negative bacteria. Herein, we expand our
exploration of kinase inhibitors in Gram-negative bacilli utilizing
three commercially available kinase inhibitor libraries and, ultimately,
identify two chemical structures that potentiate colistin (polymyxin
E) in multiple strains. We report IMD-0354, an inhibitor of IKK-β,
as a markedly effective adjuvant in colistin-resistant bacteria and
also describe AR-12 (OSU-03012), an inhibitor of pyruvate dehydrogenase
kinase-1 (PDK-1), as a potentiator in colistin-sensitive strains.
This report comprises the first description of the novel cross-reactivity
of these molecules.