Derazantinib Inhibits the Planktonic Growth and Biofilm Formation of Staphylococcus aureus by Binding Membrane Phospholipids and Disrupting the Cell Membrane

Derazantinib (DZB), a pan-fibroblast growth factor receptor (FGFR) inhibitor, exhibits potent activity against FGFR1-3 kinases and has been clinically approved for antitumor therapy. However, its Antibacterial properties remain unknown. Here, we demonstrated that DZB displays broad-spectrum activity against Staphylococcus aureus (S. aureus), with minimum inhibitory concentrations (MICs) ranging from 6.25 to 25 μM. DZB exhibited more rapid and stronger bactericidal activity against planktonic cells of both MSSA and MRSA compared to vancomycin. DZB at 6.25 μM robustly inhibited biofilm formation and even eradicated mature biofilms. Global proteomic profiling revealed that DZB's Antibacterial mechanism might involve disruption of microbial glycolysis/gluconeogenesis pathways. Furthermore, in vitro selection of DZB-induced resistant S. aureus resulted in a 2-fold increase in MIC, and whole-genome Sequencing of this derivative isolate identified amino acid mutations in membrane-associated proteins. DZB was found to compromise Bacterial membrane integrity, as evidenced by increased membrane permeability, and the membrane damage was also confirmed by scanning electron microscopy (SEM). The Antibacterial activity of DZB was neutralized by the addition of exogenous phosphatidylglycerol and cardiolipin. Biolayer interferometry assays demonstrated a strong interaction between DZB and cardiolipin, suggesting membrane phospholipid targeting as a key mechanism. Lastly, DZB displayed a robust inhibitory effect against intracellular S. aureus SA113 and showed excellent in vivo anti-MRSA Infection in both Galleria mellonella larvae and murine Infection models. In summary, our findings established DZB as a promising anti-S. aureus agent with dual Antibacterial and antibiofilm activities by disrupting the cell membrane through targeting membrane Phospholipids.

Staphylococcus aureus; antibacterial activity; biofilm; cell membrane; derazantinib.