*2.2.1 VISA*

The first vancomycin intermediate *S. aureus* was reported in 1997 from Japan with MIC value of 8 μg/ml [17]. VISA strains are generally preceded from heterogeneous Vancomycin resistant *S. aureus* (hVISA). hVISA is the precursor of VISA and is composed of cell subpopulations with various degrees of Vancomycin resistance. Vancomycin-intermediate *S. aureus* (VISA) are those isolates with a MIC between 4 and 8 mg/l, whereas heterogeneous VISA (hVISA) strains appear to be sensitive to Vancomycin with susceptible range of 1–2 mg/l, but containing subpopulation of Vancomycin-intermediate daughter cells (MIC ≥4 μg/ml). Vancomycin-resistant *S. aureus* (VRSA) are defined as those having MICs of at least 16 mg/l [16]. This means that, in the same culture plate, some strains are sensitive and some strains show Intermediate resistance to Vancomycin which may lead to treatment failure [18]. The underlying mechanism is still not completely known. However, scientists have put some efforts to identify the genetic determininants of VISA via different molecular identification methods such as comparative genomics, proteomics, transcriptomics etc. This lead to identification of genes responsible for VISA such as WalKR, GraSR, and VraSR [19]. The following are the fundamental characteristics of VISA phenotypes [14]:


GraRs gene regulates the transcription of cell wall biosynthesis and specifically up-regulates the genes responsible for capsule biosynthesis operon. It also up-regulates the *dlt* operon and the *mprF*/*fmtC* genes, which are linked to teichoic acid alanylation and alters the cell wall charge. Moreover, the GraRS mutation can modify the expression of *rot* (repressor of toxins) and *agr* (accessory gene regulator). This leads to downstream effect of global regulators [20].
