Drug-induced metabolic remodeling of immune cell repertoire generates an effective broad-range antimicrobial effect [scRNA-Seq]

Multiple mechanisms of immunity must be coordinated for the successful defense against a comprehensive range of pathogens, yet how broad-spectrum antipathogens act through these mechanisms remains largely elusive. Here, we used systems biology approaches to understand human immune cell reorganization at the single-cell level using a novel silane derivative, K21, which is effective against viruses, bacteria, and fungal infections. K21 significantly induced pro-inflammatory macrophages originating from both M1 and M2c macrophages without changing their ability to secrete respective cytokines. K21 decreased a specific subtype of M1 macrophages and CXCL4-induced M2-like macrophages, currently referred to as M4 macrophages, that play a critical role in solid cancers and fibrosis. K21-mediated immune cell remodeling was observed only in a complex multicellular co-culture environment, suggesting the interplay of various cell-derived components. K21 improved mitochondrial health by enhancing mitochondrial recycling via mitophagy. Similar treatment of the in vivo model organism C. elegans induced mitophagy and extended lifespan, suggesting evolutionary conservation of the mechanism. Our work demonstrates that a drug that remodels metabolism can shape the immune cell repertoire, which could aid in the development of more effective antimicrobials and potentially prevent the emergence of drug-resistant pathogens.