Potential of training of anti- <i>Staphylococcus aureus</i> therapeutic phages against <i>Staphylococcus epidermidis</i> multidrug-resistant isolates is restricted by inter- and intra-sequence type specificity

Phage therapy appears to be a promising approach to tackle multidrug-resistant bacteria, including staphylococci. However, most anti-staphylococcal phages have been characterized in <i>Staphylococcus aureus</i>, while a limited number of studies investigated phage activity against <i>S. epidermidis</i>. We studied the potential of phage training to extend the host range of two types of anti-<i>S</i>. <i>aureus</i> phages against <i>S. epidermidis</i> isolates. The Appelmans protocol was applied to a mixture of <i>Kayvirus</i> and a mixture of <i>Silviavirus</i> phages repeatedly exposed to seven <i>S</i>. <i>epidermidis</i> strains representative of nosocomial-associated sequence types (ST), including the world-wide disseminated ST2. We observed increased activity only for the <i>Kayvirus</i> 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 of the same ST. Of note, 16/47 ST2 strains were susceptible to one of the groups of trained phages. A comparative genomic analysis of ancestral and trained phage genomes, conducted to identify potential bacterial determinants of such specific activity, found numerous recombination events between two of the three ancestors. However, a small number of trained phage genes had nucleotide sequence modifications impacting the corresponding protein compared to ancestral phages, two to four of them per phage genome being specific of each group of phage subpopulations exhibiting different host range. The results suggest that anti-<i>S</i>. <i>aureus</i> phages can be adapted to <i>S. epidermidis</i> isolates but with inter- and intra-ST specificity.Importance<i>S. epidermidis</i> is increasingly recognized as a threat for public health. Its clinical importance is notably related to multidrug resistance. Phage therapy is one of the most promising alternative therapeutic strategies to antibiotics. Nonetheless, only very few phages active against this bacterial species have been described. In the present study, we showed that phage training can be used to extend the host range of polyvalent <i>Kayvirus</i> phages within the <i>Staphylococcus</i> genera to include <i>S. epidermidis</i> species. In the context of rapid development of phage therapy, <i>in vitro</i> forced adaptation of previously characterized phages could be an appealing alternative to fastidious repeated isolation of new phages to improve the therapeutic potential of a phage collection.