Single nucleotide switches confer bacteriophage resistance to Pseudomonas protegens

Phage therapy offers a promising strategy against bacterial pathogens in medicine and agriculture, but the rise of phage-resistant bacteria presents a significant challenge to its sustainability. Here, we used an environmental model bacterium, Pseudomonas protegens CHA0, to investigate phage resistance mechanisms in laboratory conditions through genomic analysis of four phage-resistant variants (C2, C4, C17, C18). Whole-genome sequencing revealed frequent deletions, insertions, and single nucleotide substitutions, particularly in genes encoding enzymes involved in cell surface modifications. The T428P mutation in AlgC, a phosphoglucomutase, and the P229T substitution in YkcC, a glycosyltransferase, each conferred resistance by potentially altering phage receptor accessibility while preserving bacterial fitness. These findings suggest that subtle mutations in surface-modifying enzymes enable phage resistance by modifying phage-receptor accessibility while maintaining bacterial growth, highlighting adaptive mechanisms in bacterial phage interactions. Further structural analysis is needed to fully understand these mutation-driven resistance mechanisms.