Signal transduction allows bacteria to respond to environmental perturbations. The main mechanisms for bacterial signaling are two-component systems (TCSs), comprised of histidine kinases (HKs) and response regulators (RRs). Extracellular signals activate HKs, inducing autophosphorylation of a conserved histidine. The phosphate group is subsequently transferred to a cognate RR, eliciting responses such as quorum sensing, antibiotic resistance, or virulence. We are developing chemical probes to enable exploration of HK activity by pursuing a design based upon ATP. However, our compound features a modified ?-phosphate group that facilitates detection of the phosphohistidine species formed by active HKs. Moreover, we have shown its transfer to cognate RR. We are presently exploring the probe's use in proteomes to elucidate HK regulation in bacteria. Additionally, we are generating a fluorescence polarization assay to enable high-throughput screening of small-molecule libraries for HK inhibition. Together, these objectives will facilitate a better understanding of TCS activity in bacteria.

Chemical probes for histidine kinase profiling and inhibitor discovery

244th National Meeting (2012)

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