Conquering CRISPR: how phages overcome bacterial adaptive immunity

The rise of antibiotic-resistant bacteria has led to renewed interest in the use of their natural enemies, phages, for the prevention and treatment of infections. However, phage therapy requires detailed knowledge of the interactions between these entities. Bacteria defend themselves against phage predation with a large repertoire of defences. Among these, CRISPR–Cas systems stand out due to their adaptive character, mechanistic complexity and diversity, and present a significant hurdle for phage infection. Here, we provide an overview of how phages can circumvent CRISPR–Cas defence, ranging from target sequence mutations and DNA modifications to anti-CRISPR proteins and nucleus-like protective structures. An in-depth understanding of these phage evasion strategies is crucial for the successful development of phage therapy applications.