Structure‐Guided Discovery of a Potent Inhibitor of the Ferric Citrate Binding Protein FecB in <i>Vibrio</i> Bacteria

Abstract Infections caused by Gram‐negative bacteria present a significant risk to human health worldwide. Novel strategies are needed to deal with the challenge caused by drug‐resistant bacteria. Here, we report a new approach to combat infections by targeting iron‐binding proteins to suppress bacterial growth. We investigated the function of the conserved periplasmic binding protein FecB from Vibrio alginolyticus . FecB was known to play a crucial role in the bacterial growth and to relate with biofilm formation. We then solved the crystal structures and elucidated the binding mechanism of FecB with ferric ion chelated by citrate. The results indicated that FecB binds weakly to one citrate molecule and strongly to the Fe 3+ ‐(citrate) 2 complex. Based on these results, a structure‐based virtual screening approach was conducted against FecB to identify small molecules that block ferric citrate uptake. Further evaluations in vivo and in vitro demonstrated that salvianolic acid C significantly suppressed bacterial growth, indicating that targeting bacterial nutrient absorption is a promising strategy for identifying potential antibacterial drugs.