To respond to the environment, bacteria rely on phophosignaling pathways mediated by histidine kinases, suggesting these enzymes are promising targets for novel antibiotics because they play central roles in bacterial physiology. Upon activation from an extracellular signal, histidine kinases catalyze the transfer of phosphate from ATP to a conserved histidine residue. ATP competitive inhibitors are one method for inhibiting these kinases, and this strategy has the potential to globally inhibit all bacterial histidine kinases, thereby affording broad-spectrum antibacterial activity. The ATP binding domain of histidine kinases is the Bergerat fold, which is also found in the Hsp90 protein family. To find ATP competitive lead molecules of histidine kinases, we screened known ATP competitive Hsp90 inhibitors against CckA, an essential histidine kinase in <i>Caulobacter crescentus </i>that controls cell growth. We found two initial hits. We report our progress toward developing these hits into potent histidine kinase inhibitors and our characterization of the efficacy of these molecules against multiple histidine kinases.

Hsp90 inhibitors as lead molecules for histidine kinase inhibition: Toward novel antibiotics

251st National Meeting (2016)

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