Variable fitness effects of bacteriophage resistance mutations in <i>Escherichia coli:</i> implications for phage therapy

This study isolated more than 50 phage-resistant mutants from both <i>in vitro</i> and <i>in vivo</i> conditions, exposing an extra-intestinal pathogenic <i>Escherichia coli</i> strain to a single virulent phage. The characterization of these clones revealed several key findings: (1) mutations occurring during phage treatment affect the same pathways as those identified <i>in vitro</i>; (2) the resistance mechanisms are associated with the modification of two cell-wall components, with one involving receptor deletion (phage-specific mechanism) and the other, less frequent, involving receptor masking (phage-nonspecific mechanism); (3) an <i>in vivo</i> virulence assay demonstrated that the absence of the receptor abolishes virulence while masking the receptor preserves it; and (4) clones with a resistance mechanism nonspecific to a particular phage can remain susceptible to other phages. This supports the idea of incorporating diverse phages into therapeutic cocktails designed to collectively target both wild-type and phage-resistant strains, including those with resistance mechanisms nonspecific to a phage.