# Phase Therapy: Consider the Past, Embrace the Future
## 3 Strategies for Phage Therapy
### _Phage-Derived Enzymes_  
In the life cycle of phages, a number of enzymes encoded in phage genomes could breach bacterial cells, such as virion-associated peptidoglycan hydrolases (VAPGH), endolysins, and polysaccharide depolymerases. Virion-associated peptidoglycan hydrolases (VAPGH) mostly located on the phage base plate punch holes through degrading the peptidoglycan of the bacterial cell wall to inject the phage genetic material during the adsorption of phages [57]. VAPGHs are specific and stable; therefore, they are potential candidates as new antimicrobials, but they are rarely studied and applied in clinical treatment [28]. In contrast, at the end of the lytic cycle, phages lyse host bacteria and release the viral progeny, which mainly rely on the action of their own lytic enzymes. As early as 1958, [PERSON] et al. discovered a class of proteins encoded by a phage that can lyse bacteria, and named it endolysin (lysin); more importantly, they found that the lysins obtained from either the U.V. induction of lysogenic _Escherichia coli_ K12 or the infection of sensitive _E. coli_ K12 with \(\lambda\) phages also were able to lyse _E. coli_ K12 cells [58]. Phage lysin, as a class of peptidoglycan hydrolases, can directly destroy the peptidoglycan of a bacterial cell wall [59]. Phage lysin is also considered a potential alternative to antibiotics and exhibits some obvious advantages over phages. First of all, phage lysins are highly species specific, and they do not cause damage to the body's cells, or disrupt the homeostasis of normal bacteria [39]. Second, compared with phages, lysins have a broader lysis spectrum, and they are less likely to lead to the emergence of a resistant pathogen. [PERSON] et al. successfully purified a lysin encoded by an _S. aureus_ bacteriophage phi MR11; this lysin could quickly and completely lyse cells of many tested _S. aureus_ strains, including methicillin-resistant _S. aureus_ (MRSA) and vancomycin-resistant _S. aureus_ (VRSA), and the lysin resistance was not observed [39; 60; 61]. Finally, as a kind of protein, phage lysin's physicochemical properties lysins spectrum are easier to be improved.  
In addition to the VAPGH and endolysins, many bacteriophages encode depolymerases [62; 63]. Phage-encoded depolymerases hydrolyze polysaccharide compounds of bacteria, such as capsule, lipopolysaccharide, or extracellular polysaccharides of biofilms [64; 65]. Bacterial capsule and biofilm help bacteria to resist the action of antibiotics, disinfectants, and phagocytes. Therefore, using depolymerases to destroy these protective barriers of pathogens can efficiently improve the therapeutic effect of bacterial infection. For example, a polysaccharide depolymerase (Dpo48) from the _A. baumannii_ phage IME200 was found to degrade the capsule of bacteria and to have the same activity spectrum with its parental phage [46]. [PERSON] et al. found that a phage tail-associated depolymerase (protein gp52) could enhance the immune system against _Providencia sturtii_ in a human serum model [49]. Some studies have also confirmed that certain new lysins can effectively protect animals from pathogens such as beta-hemolytic _Streptococcus agalactiae_ and multidrug-resistant _A. baumannii_[34; 40]. All these findings suggest that phage-derived enzymes are potential antimicrobials and promising alternatives to antibiotics. Moreover, the convenient industrial production of enzymes will promote their applications.