Training of anti-Staphylococcus aureus phages against S. epidermidis multidrug-resistant isolates is associated with inter- and intra-sequence type host range specificity

Phage therapy is considered a promising option in the face of antibiotic multidrug-resistant bacteria, including staphylococci. However, most anti-staphylococcal phages have been characterized in S. aureus, while a limited number of studies investigated phage activity against S. epidermidis. We studied the potential of phage training to extend the host range of two types of anti-S. aureus phages against S. epidermidis isolates. The Appelmans protocol was applied to a mixture of Kayvirus and a mixture of Silviavirus phages repeatedly exposed to seven S. epidermidis strains representative of nosocomial-associated sequence types (ST), including ST2. We observed increased activity only for the Kayvirus mixture against two of these strains (ST2 or ST35). Phage subpopulations isolated from the training mixture using these two strains (five/strain) exhibited different evolved phenotypes, active only against their isolation strain or strains against which they had never been exposed but of the same ST. Of note, 16/47 ST2 strains were susceptible to one of the groups of trained phages. Genomic analyses were conducted to identify potential bacterial determinants of this specificity. A comparative analysis of ancestral and trained phage genomes found numerous recombination events between two of the three ancestors. A small number of trained phage genes had nucleotide sequence modifications impacting the corresponding protein compared to ancestral phages, two-to-four of them being specific of each group of phage subpopulations exhibiting different host range. The results suggest that anti-S. aureus phages can be adapted to S. epidermidis isolates but with inter- and intra-ST specificity.