Characterization of an Antibacterial Agent Targeting Ferrous Iron Transport Protein FeoB against Staphylococcus aureus and Gram-Positive Bacteria

The emergence of multidrug-resistant Staphylococcus aureus strains has become a serious clinical problem. Iron is absolutely required for the bacterial growth, virulence associated with colonization, and survival from the host immune system. The FeoB protein is a major iron permease in bacterial ferrous iron transport systems (Feo) that has been shown to play a crucial role in virulence of some pathogenic bacteria. However, FeoB is still uncharacterized in Gram-positive pathogens, and its effects on S. aureus pathogenesis are unknown. In this study, we identified a novel inhibitor, GW3965·HCl, that targets FeoB in S. aureus . The molecule effectively inhibited FeoB in vitro enzyme activity, bacterial growth, and virulence factor expression. Genome-editing and metabolomic analyses revealed that GW3965·HCl inhibited FeoB function and affected the associated mechanisms with reduced iron availability in S. aureus . Gentamicin resistance and Caenorhabditis elegans infection assays further demonstrated the power of GW3965·HCl as a safe and efficient antibacterial agent. In addition to S. aureus, GW3965·HCl also presented its effectiveness on inhibition of the FeoB activity and growth of Gram-positive bacteria. This novel inhibitor will provide new insight for developing a next-generation antibacterial therapy.