## 3 Discussion
These factors may ultimately impact the pathogenesis and treatment outcome in MRSA endovascular infection. Lipid metabolism genes (e.g., _gehB_, and _ugtP_) were reported to promote biofilm formation and host cell invasion [22]. We found that the mutation of these genes had significantly decreased EC damage vs. JE2 parental strain. These results may indicate a connection between lipid metabolism and EC damage. Genetic factors associated with nucleotides metabolism (e.g., _purN_) were also found to positively impact the EC damage. _purN_ encodes the enzyme in _de novo_ purine biosynthesis pathway which generates ATP and GTP that can be processed to stringent response alarmone, guanosine 3\({}^{\prime}\)-diphosphate-5-di(tri)phosphate ((p)ppGpp) [15]. Increased GTP and subsequent (p)ppGpp levels lead to enhanced persistent bacteremia (PB) phenotypes including a higher EC damage rate [15]. It is worthwhile to mention, genes related to staphylococcal cell-wall peptidoglycan biosynthesis (e.g., _murA_) and cell division (e.g., _scdA_) showed significant positive effects on EC damage. Cell-wall synthesis has long been considered an important target for novel anti-_S. aureus_ agents [23; 24], and our findings have implications for the approach. In the genetic information processing pathways, genes involved in homologous recombination (e.g., _recD_, and _recG_), ribosome (e.g., _rrIA_, and _rpsA_), and protein export (e.g., _lspA_, and _tatA_) were identified to affect EC damage. For example, the signal peptidase encoded by _lspA_ is required for biogenesis of bacterial lipoproteins, and failure to produce mature lipoproteins has previously been shown to impair pathogenicity and immune-modulating [25]. The results suggested that some genes related to genetic information processing also play a role in human EC damage. The inactivation of genes involved in environmental information processing pathways such as ABC transporter (e.g., _fluaB_, and _mntC_) and two-component system (e.g., _saeSR_, and _arISR_) also decreased EC damage. These findings were in accordance with previous studies showing the presence of these gene products was associated with higher in vivo virulence potential vs. their respective WT strains [13; 26; 27; 28]. Genes involved in cellular process, specifically quorum sensing (e.g., _agr_, and _luxS_), were identified to contribute to the EC damage. It is well known that quorum sensing via _agr_ plays a central role in the pathogenesis of _S. aureus_. Under high cell density, _agr_ is responsible for the increased expression of many toxins which may impact the EC damage [16], while the function of _luxS_ in _S. aureus_ has not been well investigated. Genes unidentified in the KEGG pathways also showed a positive impact on the HMEC-1 damage in the current study. Some of these genes have been previously demonstrated to correlate with biofilm formation (e.g., _xcrC_), oxidative killing (e.g., _nfu_, and _yjbl_), hemolysis (e.g., _hlb_), and heat shock (e.g., _lslU_) [29; 30; 31; 32]. In addition, few phage genes (SAUSA300_1433, SAUSA300_1934, SAUSA300_1936, SAUSA300_1968) were also shown impacts on the HMEC-1 damage. Mutants of six genes had elevated EC damage indicating their negative impact on the EC damage. Among these genes, _mepA_ encodes a multidrug efflux pump protein [33], _azoR_ encodes quinone reductase [34], _moAD_ encodes one of the subunits of molybden synthase involved in sulfur relay system pathway [35], gene SAUSA300_1197 encodes glutathione peroxidase. Further investigations related to the relationship between these genes and EC damage are needed.