# Global Transcriptomic Response of _Staphylococcus aureus_ to Viulent Bacteriophage Infection
## 1 Introduction  
_Staphylococcus aureus_ is an opportunistic bacterial pathogen that colonizes up to 30% of the human population [1]. Due to variations in virulence factors, _S. aureus_ isolates may cause a wide range of diseases, from skin and soft tissue infections to such dangerous diseases as pneumonia, meningitis, and osteomyelitis [2]. Furthermore, the spread of methicillin-resistant Staphylococcus aureus (MRSA) strains complicates disease prognosis by making \(\beta\) -lactam antibiotics ineffective [2]. According to the WHO, the prevalence of MRSA exceeds 20% in some countries [3], and the mortality rate of infections caused by MRSA strains is higher than those caused by methicillin-sensitive _S. aureus_[4]. In addition, multidrug-resistant (MDR) _S. aureus_ strains have been increasingly identified in recent years. In European countries, the proportion of _S. aureus_ strains resistant to more than one antibiotic accounts for 10% [5]. A promising alternative for the treatment of infections caused by antibiotic-resistant bacteria is phage therapy. Bacteriophages are the most abundant biological objects in the water column of the world's oceans and are the second-largest biomass component after prokaryotes. Being natural predators, they control the bacterial population. A key feature of bacteriophages is their strict selectivity for bacteria. Phages affect only bacterial host cells as targets and cannot infect eukaryotic cells. Their efficacy has been demonstrated in avariety of animal models [6; 7]. In critical situations, due to the lack of effective antibiotics, bacteriophages can be deemed the treatment of last resort [8]. Nowadays, staphylococcal keyviruses (genus _Kayvirus_; subfamily _Twortvirinae_; family _Herelleviridae_) are among the most widely used bacteriophages as therapeutic agents [9]. Bacteriophages of this group are closely related and are obligatorily lytic. Staphylococcus have a high lytic capacity, causing lysis of more than 85% of clinical isolates, including MDR isolates [10; 11; 12; 13], and show promising results in the treatment of diseases caused by _S. aureus_[14; 15; 16]. Although phage therapy is a promising alternative, its regulation and successful mass application require a thorough understanding of the fundamental mechanisms of the interaction between the phage and the host. Advances in omics technologies provide new opportunities in this area, with transcriptome analysis as the most appropriate method to investigate these interactions [17; 18; 19; 20; 21; 22]. Such studies have previously been carried out for phages of _Pseudomonas aeruginosa_[17; 18], _Acinetobacter baumannii_[20], _Bacillus subtilis_[19], _Escherichia coli_[23], _Yersinia enterocolitica_[22], and other bacterial host species. However, in the case of _S. aureus_, data on the transcriptional analysis of the relationship between bacteriophages and their hosts are still insufficient. The existing study on this issue is limited to temperate bacteriophages [24]. In previous reports, we characterized a virulent vB_SauM-515A1 staphylophage isolated from a commercial therapeutic cocktail [12]. The phage demonstrated a wide host range and successfully lysed 85.3% of clinical _S. aureus_ strains. Based on transmission electron microscopy and whole-genome sequencing data, vB_SauM-515A1 was identified as a member of the _Herelleviridae_ family [25]. The phage genome comprises 238 putative open reading frames (ORFs) and 4 tRNAs (tRNA-Met, tRNA-Trp, tRNA-Phe, and tRNA-Asp) and has no genes for integrases, toxins, or virulence-associated factors. Transcriptional profiling of the vB_SauM-515A1 phage upon _S. aureus_ strain SA515 infection revealed that 35 transcriptional units in the genome are regulated by 58 early and 12 late promoters. Early promoters are represented by the strong \(\sigma^{70}\) promoters and control 26 transcriptional units; the late promoters only regulate the expression of four transcriptional units. The remaining five transcriptional units were controlled by both early and late promoters.