Metals & Immunity

The global public health problems of infectious disease and antibiotic resistance motivate our biochemical and bioinorganic investigations of the host/pathogen interaction. In one thrust, we are inspired by the structures and biological functions of human host-defense peptides/proteins and we aim to achieve molecular-level and quantitative depictions of how these biomolecules contribute to innate immunity and physiology. Such knowledge is required to test and revise working models, understand biological function, and guide the development of new antibacterial therapies. As bioinorganic chemists, our research program addresses the accepted or hypothesized roles for host-defense proteins in the biology of transition metals. In one area, we are currently investigating the metal-sequestering antimicrobial protein calprotectin. Our central hypotheses are that calprotectin (i) contributes to human physiology in multiple contexts, (ii) responds to local environmental stimuli and thereby exist in multiple structural forms that have particular physiological roles, and (iii) participates in the homeostasis of metals in broad terms. In a related initiative, we aim to harness microbial metal transport machinery to target antibiotics and other cargos to Gram-negative bacterial species. Our approach is inspired by siderophores, small-molecule iron chelators produced and utilized by many bacterial species for iron acquisition in the vertebrate host. We are harnessing siderophore-receptor interactions and native siderophore scaffolds to achieve efficient cargo delivery across the outer membrane permeability barrier of Gram-negative organisms and target virulence. In total, our research program affords paradigms for discovering and elucidating new bioinorganic chemistry, advancing fundamental understanding of human innate immunity and microbial pathogenesis, and providing new molecules with potential therapeutic application.