# Current Promising Strategies against Antibiotic-Resistant Bacterial Infections
## 4 Developing Alternatives to Antibiotics
### Bacteriophages and Their Encoded Endolysins  
In terms of treating bacterial infections, bacteriophage (phage) therapies preceded antibiotic treatment [88]. Phages are duplodnaviria viruses that can exclusively lyse bacteria without harming host cells (Figure 4). Since the introduction of broad-spectrum antibiotics in the 1940s, the development of phage therapy has halted. However, with the emergence of ARB, phage therapy is regaining attention. Currently, several products based on phage therapy are commercially available in some Eastern European countries, while a number of clinical or preclinical studies on phage therapy have been conducted in different countries worldwide. One randomized phase 1/2 trial in France and Belgium evaluated the efficacy and tolerability of a cocktail of phages in patients with _P. aeruginosa_ wound infection [89]. Unfortunately, due to the highly unexpected low concentration of phages after manufacturing, this phage therapy showed a slower efficiency in decreasing bacterial load than the standard treatment of burn wounds and needs to be further fine-tuned by increasing phage concentration and evaluated in a large sample of participants [89]. Nonetheless, several case reports originating from China and the United States have shown that phage administration with or without antibiotic treatments could protect patients against multidrug-resistant _A. baumantii_ infection [90; 91; 92], demonstrating the potential of phage therapy against ADR infections in appropriate doses. However, phage bacterial resistance and their immunogenicity are two additional unresolved drawbacks of phage therapy.  
Phages employ multiple steps to perform their lytic cycle, primarily by utilizing endolysins, the enzymes that lyse the bacteria by degrading peptidoglycan [93]. Endolysins can be designed to have specificity towards different species of GNBPs and GPBPs. A study reported four recombinant endolysins that could effectively lyse one hundred GNBPs, including multidrug-resistant _K. pneumoniae, Salmonella, P. aeruginosa, E. coli, A. baumantii_, and _Enterobacter_ spp. strains [94]. An endolysin (Ply6A3) directly purified from phages showed high antibacterial activity against _A. baumantii, E. coli_, and MRSA [95]. A new anti-MRSA endolysin, rSAL-1, has been developed and tested as a drug (SAL200), which showed no serious adverse effects in phase-1 of clinical trials [96]. SAL200 is the first endolysin-based drug to be approved for treating human skin infections caused by _S. aureus_, including MRSA [97]. This therapy was highly effective on both chronic and recurrent _S. aureus_-related dermatoses without selecting for bacterial resistance after long-term daily treatment. Another endolysin-based drug, Exebacase, has been developed to treat staphylococcal bloodstream infections, by ContraFect Corporation and is currently in phase 3 of clinical studies [98]. During phase 2, with the aid of standard care antibiotics, a single intravenous infusion of this drug could help patients to combat _S. aureus_ bacteria and endocarditis [99].