Training of anti-Staphylococcus aureus phages against  S. epidermidis multidrug resistant isolates is associated with  inter- and intra-sequence types host range specificity
Phage therapy is considered as a promising option to face the growing threat of antibiotic multi-resistant bacteria, including staphylococci. However, most of the anti-staphylococcal phages have been characterized in S. aureus strains, while only a limited number of studies reported phage activity against S. epidermidis.   We investigated 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 two mixtures of Kayvirus or Silviavirus phages repeatedly exposed to seven S. epidermidis strains representative of nosocomial-associated sequence types (ST), including the prevailing 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, being 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. Finally, comparative analysis of ancestral and trained phage genomes showed numerous recombinations events between two of the three ancestors. Interestingly, different mosaic profiles could be associated to the same evolved phenotype. A small number of trained phage genes showed nucleotide sequence modifications impacting the corresponding protein compared to ancestral phages, two or four of them being specific of each group of phage subpopulations exhibiting different host range.  Our results suggest that anti-S. aureus phages can be adapted to S. epidermidis isolates but with inter- and intra-ST specificity.