Proteomic analysis of murine macrophages mitochondria and lysosomes reveal Cathepsin D as a potential broad-spectrum antimicrobial protein.

Bacterial resistance to antibiotics has become increasingly widespread, posing a serious threat to human life and health. Macrophages in the host's natural immune system can directly destroy most of bacteria. Therefore, exploring the function of macrophages' mitochondria and lysosomes in killing bacteria might help us overcome the problem of bacterial resistance. We used mass spectrometry to analyze the dynamic expression landscape of mitochondrial and lysosomal proteins in macrophages upon infection with Listeria monocytogenes, Staphylococcus aureus, Bacillus subtilis, Escherichia coli, and Pseudomonas aeruginosa. We discovered that Cathepsin D (Ctsd) is up-regulated at the protein level during infection by all five bacteria. Ctsd inhibitor and knockout experiments confirmed that Ctsd is a potential broad-spectrum antibacterial protein. Ctsd should be investigated further as a potential drug target for new antibacterial treatments.