In S. pneumoniae, there are two proteins that share responsibility for Zn2+ homeostasis, one of them is the Adhesin Competence Repressor (AdcR), a Zn2+ responsive repressor and a member of the MarR family of metalloproteins. AdcR directly represses genes including adcRCBA, adcAII-phtD, phtA, phtB, and phtE in the presence of Zn2+ - these lead to inhibition of Zn2+ uptake when activated. AdcR has been crystallized and determined to contain two metal centers in each monomeric unit capable of binding divalent metal species. One of the metal binding sites contains cysteine residue, which is key to metal ion binding dependent allosteric changes in the protein that induce DNA binding. Here we report our efforts to target this Cys for chemical modification and characterize how Cys-modification modulates both Zn2+ and DNA binding. This small molecule inhibition approach to perturbing Zn2+ ion homeostasis in S. pneumonia will be studied using both in vivo and in vitro methods.

Targeting the cystine dependent zinc-binding domain of transcription factor AdcR

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