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

TL;DR

This paper shows how a drug called K21 can reshape immune cells and metabolism to fight a wide range of infections.

Contribution

The study reveals a novel mechanism by which a drug induces metabolic remodeling of immune cells to produce broad antimicrobial effects.

Findings

K21 induces pro-inflammatory pathways in macrophages without changing cytokine secretion.

K21 improves mitochondrial health through mitophagy in immune cells.

Treatment with K21 in C. elegans induces mitophagy and extends lifespan.

Abstract

Multiple mechanisms of immunity must be coordinated to defend against a comprehensive range of pathogens; however, the mechanisms by which broad-spectrum antipathogens act remain largely elusive. Here, we employed systems biology approaches to understand the organization of human immune cells at the single-cell level, as well as their reorganization in response to K21, a silane derivative effective against viral, bacterial, and fungal infections. K21 induced pro-inflammatory pathways in M1 and M2c macrophages without altering cytokine secretion, decreased a specific subtype of M1 macrophages and CXCL4-induced M2-like macrophages, and 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 mitochondria and metabolism can shape the immune cell repertoire, which could aid the development of more effective antimicrobials and prevent the emergence of drug-resistant pathogens.

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