GaSal-2: A Water-Soluble Antipseudomonal Agent Targeting the Extracellular Hemophore HasAp

Multidrug-resistant Pseudomonas aeruginosa is a critical pathogen that demands new antibiotics. During P. aeruginosa infection, the extracellular hemophore hasAp and its outer membrane receptor hasR are the most dramatically upregulated genes. The P. aeruginosa ΔhasR strain exhibits significantly reduced growth and virulence. We previously described a gallium salophen complex GaSal that demonstrated antipseudomonal potential by targeting HasAp. Here, we report the development of a water-soluble derivative, GaSal-2, which tightly binds to HasAp, blocks transcriptional activation of the bacterial cell surface signaling cascade, inhibits P. aeruginosa growth, and effectively disrupts P. aeruginosa established biofilms. Moreover, GaSal-2 is not toxic to human lung fibroblasts and hepatocytes. It has shown promising antipseudomonal effects in a murine lung infection model.