Abstract: Antibiotic resistance is a global health concern that causes over one million deaths worldwide. Understanding molecular mechanisms of bacterial pathogenesis and the innate immune response is critical for identifying new antimicrobial therapeutic approaches. My lab is interested in characterizing the underlying determinants of metal homeostasis with an eye toward creating new antimicrobial agents. One-third of the proteome is predicted to comprise metalloproteins. Metals are essential for all forms of life as they serve as enzymatic cofactors, structural stabilizers and chemical messengers. However, high concentrations of metals are toxic. Thus, maintenance of metal homeostasis is essential at the host-pathogen interface. For example, S100A12 is a high affinity transition metal binding protein that starves invading pathogens and prevents them from acquiring essential zinc, in a process termed nutritional immunity. I will present recent results from my lab that suggest zinc binding to S100A12 potentiates oligomerization and is associated with activation of inflammation through the receptor for advanced glycation end products. The importance of zinc regulation is also highlighted in the pathogenesis of the human pathogen Streptococcus agalactiae, one of the primary causes of adverse pregnancy outcomes. CadD, a metal efflux transporter is essential for S. agalactiae to resist zinc intoxication by macrophages, thereby facilitating ascending infection in a pregnant host. Together, these data demonstrate the importance of understanding metal homeostasis and provide potential pathways to overcoming antibiotic resistance.