Defensomes, counter-defensomes, and the remodeling of microbial communities.

Bacteria and mobile genetic elements (MGEs) have coevolved for billions of years in an enduring evolutionary arms race, leading to the emergence and diversification of a vast arsenal of defense and counter-defense systems. In the last recent years, high-throughput screening methods and genome-resolved metagenomics have markedly enhanced our understanding of the diversity and abundance of immune systems across cultured and uncultured microorganisms. This fueled subsequent interest in better understanding the dynamic tri-kingdom interplay between bacteria, bacteriophages, and eukaryotic cells, and led to renewed efforts to improve alternative antibacterial phage-based therapies. Here, we discuss the evolutionary and ecological dynamics underlying the bacteria-MGE arms race, recent findings on bacterial defensomes, MGE counter-defensomes, holodefensomes, and their key role in the development of microbiome-targeted therapies. To this end, we argue why and how highly conserved anti-MGE defense systems should be prioritized as promising targets for the development of next-generation bacterial inhibitors with broad biomedical relevance, supported by a comprehensive analysis of their distribution and diversity across bacteria.