*2.2.2 VRSA*

Vancomycin resistance is mediated by Van cluster which are found in bacteria such as S*. aureus, E.fecalis, E.faceium, Clostridium difficile*, Acintomycetes (Amycolotopsis orientalis*, Actinoplanes teichomyceticus, and* Streptomyces toyocaensis) as well as anaerobic bacteria from the human bowel flora such as *Ruminococcus* species and *Paenibacillus popilliae* [21].

Based on the Van gene, homologues Vancomycin resistance is classified into several gene (Van) clusters which encode for the enzymes which synthesize D-Alanyl-D-lactate and D-alanyl-D-serine. Eleven van gene clusters have been discovered till now, namely, *VanA, VanB, VanD, Van F, VanI, VanM, VanC, VanE, VanG, VanL, and VanN* [22].


VRSA resistance mechanism is mediated by van A operon, which is carried on the mobile genetic element (Transposon) Tn1546. VanA cluster is encoded by 5 proteins such as VanS, VanR, VanH, VanA and VanX, having the following functions;


Enterococcus spp. is the major reservoir of Vancomycin resistance and it is transferred to other bacterial species by the horizontal gene transfer method of bacterial conjugation. The Inc18 incompatibility conjugative plasmid naturally occurs in Enterococcus but not in Staphylococci spp. The Inc18 contains pSK41-like multi-resistant conjugative plasmids. These plasmids are transferred from *E. faecalis* to *S. aureus* [25].

#### *2.2.3 Treatment challenges*

Deletion of Van cluster components has lead to recovery of Vancomycin sensitivity. This is a promising target for new drug development [26]. For example, hydroxyethylamines, posphinate and phosphonate transition-state analogues have been used for the inhibiton of VanA [27, 28]. Phosphinate based covalent inhibitors, and sulfur-containing compounds have been demonstrated in VanX inhibitors [29]. These inhibitors can be used in combination with Vancomycin to increase uptake of the antibiotic inside the bacterial cell [21].
