Drug-induced metabolic remodeling of immune cell repertoire generates an effective broad-range antimicrobial effect
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 the differentiation of monocytes into macrophages and dendritic cells (MoDCs), as well as the differentiation of natural killer cells (NK cells). 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 mechanism. Our work demonstrates that a drug that remodels metabolism can shape the immune cell repertoire, which could help develop more effective antimicrobials and potentially prevent the development of drug-resistance pathogens. Overall design: RNA-seq of L4-stage C. elegans nematodes following treatment (from embryogenesis through L4) with either K21 quaternary ammonium silane or vehicle control.