Zinc(II) is a micronutrient required by all known life. In both prokaryotic and eukaryotic organisms, intracellular zinc(II) concentrations are controlled by a family of transcription factors that regulate metal uptake and efflux systems. In S. pneumoniae, two proteins have been found to be responsible for Zn2+ homeostasis, namely AdcR and SczA. These proteins share little structural homology, but are both Zn2+ dependent transcription factors, where AdcR regulates Zn2+ uptake and SczA controls Zn2+ efflux. AdcR is a member of the MarR family of transcription factors and directly represses adcRCBA, adcAII-phtD, phtA, phtB, and phtE genes in the presence of Zn2+. AdcR is a dimer and contains two Zn2+ ions per monomeric unit, one of which has a water molecule in its r coordination sphere. Here we report our initial efforts to displace this water molecule with small molecules known to coordinate to zinc(II) ions in vitro and in vivo. A family of phenylsulfonamides have shown promise as AdcR binding molecules. Full characterization of the thermodynamic parameters for each of these binding events were measured using common biophysical techniques, which allow some insight into how the structure of these impact efficiency. Each of the AdcR/phenylsulfonamide complexes was screened against the AdcR binding domain to determine if these small molecules can disrupt the equilibria required for zinc(II) homeostasis. The antimicrobial activity of these agents was also monitored against laboratory strains of S. pneumoniae.

Binding small molecules to the zinc(II) dependent transcription factor AdcR

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