Bacterial Defense and Phage Counterdefense: Unraveling the Molecular Basis of Phage Resistance

Abstract Phage therapy represents a promising strategy against multidrug-resistant bacteria, but its clinical effectiveness is increasingly compromised by the emergence of phage-resistant traits (PRTs). This resistance develops through multiple interconnected mechanisms that operate at different levels of bacterial defense. At the primary level, mutations in phage receptors, cell surface glycoconjugates (lipopolysaccharide, capsule polysaccharide, exopolysaccharide), outer membrane proteins, drug efflux pumps, and surface layer proteins provide the first line of defense by preventing phage adsorption. These receptors are highly diverse across Gram-negative bacteria, Gram-positive bacteria, and acid-fast bacteria, with PRT being particularly dominant in Gram-negative species. At the secondary level, bacteria deploy sophisticated antiphage defense (APD) systems, including CRISPR-Cas, restriction-modification systems, and abortive infection mechanisms. The recent discovery of over 150 distinct APD systems underscores the remarkable complexity of bacterial immunity. Concurrently, bacteriophages have evolved anti-antiphage defense (AAPD) systems to counter bacterial immunity, establishing a dynamic coevolutionary arms race. This continuous interplay between APD diversification and AAPD counteradaptation drives the rapid emergence of PRT, which threatens the long-term viability of phage therapy. This systematic review examines the molecular basis of phage resistance across diverse bacterial taxa, analyzes the evolutionary and coevolutionary forces shaping APD and AAPD systems, and highlights previously overlooked aspects of phage–bacteria interactions. By integrating these perspectives, we aim to inform strategies for advancing modern phage therapy and guiding future research directions.