Table 2.
The application of phage-derived enzymes in animal models
| Pathogen | Enzyme | Model | Delivery route | Dose used | Outcome | Reference |
|---|---|---|---|---|---|---|
| Phage lysins | ||||||
| Streptococcus pneumoniae | Pal amidase from pneumococcal phage Dp-1 | Mouse model of nasopharyngeal colonization | Topical nasal and pharyngeal administration | Single dose of 1400 U or 700 U | Bacteria eradication | (Loeffler et al. 2001) |
| Cpl-1 lysozyme from pneumococcal phage Cp-1 | Mouse model of bacteremia and nasopharyngeal colonization | Intravenous injection and topical nasal administration | Single dose of 2000 μg | Bacterial eradication; 80% of animals protected from death | (Loeffler et al. 2003) | |
| Rat model of pneumococcal endocarditis and bacteremia | Intravenous injection | 10 mg/kg, followed by a continuous infusion of 5 mg/kg/h for 6 h or 250 mg/kg, followed by continuous infusion of 250 mg/kg/h for 6 h | Bacteria eradication obtained with a high dose (250 mg/kg) | (Entenza et al. 2005) | ||
| Non-invasive mouse model of nasal mucosa infection | Topical intranasal administration | Two doses of 1000 μg | Bacteria eradication in 90% of animals; 100% prevention of acute otitis media | (McCullers et al. 2007) | ||
| Rat model of meningitis | Intracisternal injection | Single dose of 20 mg/kg for intracisternal injection and 200 mg/kg for intraperitoneal administration | Bacterial cfu reduction of 3 orders (intracisternal injection) and 2 orders (intraperitoneal administration) | (Grandgirard et al. 2008) | ||
| Mouse model of pneumococcal pneumonia and nasopharyngeal colonization | Intraperitoneal injection and topical intranasal administration | Multidose treatment of 1 mg | 100% of animals protected from death | (Witzenrath et al. 2009) | ||
| Mouse model of pneumococcal pneumonia and nasopharyngeal colonization | Inhalation of aerosolized Cpl-1 | Aerosolized single dose of 25 μL | 80% of animals protected from death | (Doehn et al. 2013) | ||
| Pal and Cpl-1 | Mouse model of sepsis | Intraperitoneal injection | Single dose of 200 μg; 1100 U of both enzymes | Bacteria eradication | (Jado et al. 2003) | |
| Cpl-711 chimeric lysozyme | Mouse model of bacteremia | Intraperitoneal injection | Single dose of 25–500 μg | 100% of animals protected from death | (Díez-Martínez et al. 2014) | |
| Streptococcus pyogenes | PlyC amidase, peptidase from streptococcal phage C1 | Mouse model of nasopharyngeal colonization | Topical oral and nasal administration | Single dose of different amount of enzyme (250–1000 U) | Bacteria eradication; 100% prevention against streptococcal colonization | (Nelson et al. 2001) |
| Streptococcus pyogenes | PlyPy peptidase from S. pyogenes MGAS5005 prophage | Mouse model of bacteremia | Intraperitoneal injection | Two doses of 1 mg | Bacterial cfu reduction of 2 orders; 50% of animals protected from death | (Lood et al. 2014) |
| Streptococcus agalactiae | PlyGBS peptidase, lysozyme from streptococcal phage NCTC 11261 | Mouse model of vaginal infection and oropharynx colonization | Topical intravaginal, oral and intranasal administration | Single dose of 10 U | Bacterial cfu reduction of 3 orders (vaginal infection) and 2 orders (oropharynx colonization) | (Cheng et al. 2005) |
| PlyGBS90–1 peptidase, lysozyme (modified PlyGBS) | Mouse model of vaginal infection | Topical intravaginal administration | Single dose of 30 nmol | Bacterial cfu reduction of 4 orders | (Cheng and Fischetti 2007) | |
| Streptococcus pyogenes and Staphylococcus aureus MRSA Streptococcus suis | PlySs2 amidase, peptidase from S. suis 89/1591 prophage | Mouse model of bacteremia | Intraperitoneal injection | Single dose of 2 mg | 94% and 89% of animals protected from death for S. pyogenes and MRSA, respectively | (Gilmer et al. 2013) |
| Mouse model of nasal mucosa infection | Topical intranasal administration | Single dose of 0,1 mg | Bacterial cfu reduction of > 4 orders | (Gilmer et al. 2017) | ||
| Staphylococcus aureus MRSA | MV-L amidase, peptidase from staphylococcal phage phiMR11 | Mouse model of nasal infection and bacteremia | Topical intranasal administration and intraperitoneal injection | Single dose of 310–500 U | 100% of animals protected from death | (Rashel et al. 2007) |
| ClyS chimeric amidase, peptidase | Mouse model of nasal infection and bacteremia | Topical intranasal administration and intraperitoneal injection | Single dose of 960 μg in nasal model; single dose of 2 mg in systemic model | Bacterial cfu reduction of 2 orders (nasal model); 88% of animals protected from death (systemic model) | (Daniel et al. 2010) | |
| Mouse model of skin infection | Topical skin application | Single dose of 1%, 6%, or 10% (wt/wt) | Bacterial cfu reduction of 3 orders (10% dose) | (Pastagia et al. 2011) | ||
| LysGH15 amidase, peptidase from staphylococcal phage, GH15 | Mouse model of bacteremia | Intraperitoneal injection | Single dose of 5–100 μg | Bacteria eradication; 100% of animals protected from death for ≥50 μg dose | (Gu et al. 2011a) | |
| Mouse model of bacteremia | Intraperitoneal injection | Single dose of 50 μg | Bacteria eradication | (Gu et al. 2011b) | ||
| Mouse model of bacteremia | Intravenous injection | Single dose of 50 μg | Bacterial cfu reduction of 4 orders; 100% of animals protected from death | (Zhang et al. 2016) | ||
| P-27/HP endolysin (unknown mode of action) from staphylococcal phage P-27/HP | Mouse model of bacteremia and healthy mice (safety test) | Intraperitoneal injection (for model of bacteremia) and intramuscular, subcutaneous, intravenous, and intraperitoneal injections for safety test on healthy mice | Single dose of 250 μg | Bacterial cfu reduction of 3 orders | (Gupta and Prasad 2011b) | |
| P128 chimeric VAL amidase, peptidase | Rat model of nasal infection | Topical intranasal administration | Single dose of 100 μg | Bacterial cfu reduction of ≥ 3 orders | (Paul et al. 2011) | |
| λSA2-E-Lyso-SH3b chimeric peptidase | Mouse model of mastitis | Intramammary infusion | Single dose of 25 μg | Bacterial cfu reduction of 0.63–0.81 orders | (Schmelcher et al. 2012b) | |
| Ply187AN-KSH3b chimeric peptidase | Mouse model of endophthalmitis | Intravitreal injection | Single dose of 1 μg/eye | Bacterial cfu reduction of 1 order; significant effects in protecting eyes from endophthalmitis | (Singh et al. 2014) | |
| 80αLyt2 amidase, peptidase from staphylococcal phage phi80α | Mouse model of bacteremia | Intraperitoneal injection | Single dose of 200 μg | 100% of animals protected from death | (Schmelcher et al. 2014) | |
| phi11 amidase, peptidase from staphylococcal phage phi11 | Mouse model of bacteremia | Intraperitoneal injection | Single dose of 200 μg | 100% of animals protected from death | (Schmelcher et al. 2014) | |
| LysK amidase, peptidase from staphylococcal phage K | Mouse model of bacteremia | Intraperitoneal injection | Single dose of 200 μg | 100% of animals protected from death | (Schmelcher et al. 2014) | |
| 2638A amidase, peptidase from S. aureus 2854 prophage | Mouse model of bacteremia | Intraperitoneal injection | Single dose of 200 μg | 100% of animals protected from death | (Schmelcher et al. 2014) | |
| LysWMY amidase, peptidase from staphylococcal phage phiWMY | Mouse model of bacteremia | Intraperitoneal injection | Single dose of 200 μg | 100% of animals protected from death | (Schmelcher et al. 2014) | |
| PlyTW amidase, peptidase from staphylococcal phage Twort | Mouse model of bacteremia | Intraperitoneal injection | Single dose of 200 μg | 50% of animals protected from death | (Schmelcher et al. 2014) | |
| phiSH2 amidase, peptidase from S. haemolyticus prophage phiSH2 | Mouse model of bacteremia | Intraperitoneal injection | Single dose of 200 μg | 50% of animals protected from death | (Schmelcher et al. 2014) | |
| P68 amidase, peptidase from staphylococcal phage phiP68 | Mouse model of bacteremia | Intraperitoneal injection | Single dose of ∼ 120 μg | No protecting effect (low solubility) | (Schmelcher et al. 2014) | |
| SAL-1 amidase, peptidase from the staphylococcal phage SAP-1 | Mouse model of bacteremia | Intravenous injection | Two doses of 12.5–25 mg/kg | Bacteria eradication | (Jun et al. 2013) | |
| Healthy rats and dogs (safety test) | Intravenous injection | Multiple doses of 25–100 mg/kg | No serious adverse symptoms observed | (Jun et al. 2014) | ||
| Healthy monkeys (safety test) | Intravenous injection | Multiple doses of 1–80 mg/kg | No serious adverse symptoms observed | (Jun et al. 2016) | ||
| Clinical trial on healthy male volunteers (safety test) | Intravenous injection | Single and escalating dose of 0.1–10 mg/kg | No serious adverse symptoms observed | (Jun et al. 2017) | ||
| Bacillus anthracis | PlyG amidase from B. anthracis gamma phage | Mouse model of peritonitis and bacteremia | Intravitreal injection | Single dose of 50–150 U | ~ 70% of animals protected from death | (Schuch et al. 2002) |
| PlyPH amidase from B. Anthracis prophage | Mouse model of peritonitis and bacteremia | Intraperitoneal injection | Single dose of 1.2 mg/ml | 40% of animals protected from death | (Yoong et al. 2006) | |
| Acinetobacter baumannii | PlyF307 lysozyme from Acinetobacter phage RL-2015 | Mouse model of bacteremia and mouse in vivo catheter model | Intraperitoneal injection and topical injection directly into the catheter under the skin | Single dose of 1 mg for intraperitoneal injection and two doses of 1 mg for topical application | 50% of animals protected from death; catheter biofilm reduction | (Lood et al. 2015) |
| Pseudomonas aeruginosa | Artilysin® (PVP-SE1gp146 lysozyme combining a polycationic nonapeptide) | Model of Caenorhabditis elegans gut infection | Oral and topical administration | 20 μg/ml per well (~ 10 nematodes per well) | 40–63% of animals protected from death (in the presence of 0.5 mM EDTA) | (Briers et al. 2014) |
| Phage depolymerases | ||||||
| Escherichia coli K1 | EndoE endosialidase from coliphage E | Neonatal rat model of bacteremia | Intraperitoneal injection | Single dose of 20 μg | 100% of animals protected from death | (Mushtaq et al. 2004) |
| Neonatal rat model of bacteremia | Intraperitoneal injection | Single dose of 0.25 μg | 80% of animals protected from death | (Mushtaq et al. 2004) | ||
| Salmonella Typhimurium | P22sTsp endorhamnosidase from Salmonella phage P22 | Chicken model of gastrointestinal infection | Oral administration | Multiple doses of 30 μg | Bacterial cfu reduction of ~ 1 order | (Waseh et al. 2010) |
| Klebsiella pneumoniae | K64dep capsule depolymerase from Klebsiella phage K64-1 | Mouse model of bacteremia | Intraperitoneal injection | Multiple doses of 18.75–150 μg | 100% of animals protected from death | (Pan et al. 2015) |
| depoKP36 capsule depolymerase from Klebsiella phage KP36 | Galleria mellonella infection model | Injection into the last pro-leg | Single dose of 280 μg/ml | 40% of animals protected from death | (Majkowska-Skrobek et al. 2016) | |
| Pseudomonas aeruginosa | LKA1gp49 LPS lyase from Pseudomonas phage LKA1 | Galleria mellonella infection model | Injection into the last pro-leg | Single dose of 0.05–0.5 μg | 20% of animals protected from death | (Olszak et al. 2017) |