Drug-induced metabolic remodeling promotes antimicrobial activity in macrophages and extends longevity in vivo

Multiple immune mechanisms must be coordinated to defend against a broad range of pathogens; however, the mechanisms by which broad-spectrum antipathogens act remain largely elusive. Here, we used systems biology approaches to understand the organization of human immune cells at the single-cell level and their reorganization in response to K21, a silane derivative effective against viral, bacterial, and fungal infections. K21 effectively reduced the infectivity of Enterococcus faecalis within macrophages while improving bacterial phagocytosis by human monocyte-derived macrophages, in a manner similar to that of known mitophagy inducers. K21 induced pro-inflammatory pathways in M1 and M2 macrophages without altering cytokine secretion, decreased a specific subtype of M1 macrophages and M2c macrophages, and improved mitochondrial health by enhancing mitochondrial recycling via mitophagy. Similar treatment of the model organism C. elegans induced mitophagy and extended lifespan, suggesting an evolutionarily conserved mechanism. Our work demonstrates that a drug that remodels mitochondrial metabolism can reshape the immune cell repertoire, potentially aiding the development of more effective antimicrobials and helping to prevent the emergence of drug-resistant pathogens.