DOI: 10.1128/CMR.00071-17
Article Figures & Data
Figures
- FIG 1
The cell wall structure of Gram-positive bacteria contains a thick layer of peptidoglycan that resides beyond the cytoplasmic membrane.
- FIG 2
The modular structure of the LysK endolysin, consisting of 2 enzymatically active domains (CHAP and amidase-2) and one bacterial SH3 (SH3b) cell wall-binding domain.
- FIG 3
Schematic representation of S. aureus peptidoglycan and LysK cleavage sites. The peptidoglycan is made up of sugar strands consisting of two alternating units (N-acetylmuramic acid and N-acetylglucosamine) and peptide linkers connecting these strands. Five units of glycine (Gly) act as a cross-bridge between stem peptides.
- FIG 4
Protein secretion pathway in the nisin-controlled gene expression system in L. lactis. After nisin is detected by the sensor histidine kinase protein located in the membrane (NisK), autophosphorylation of this protein occurs, followed by the transfer of its phosphatase group to the cytoplasmic response regulator NisR. NisR, which is now activated, then activates transcription via the PnisA promoter, followed by the production of a target protein, which in this case is a recombinant endolysin. Depending on the presence or absence of a specific signal peptide, the protein either is secreted into the external medium or accumulates in the cytoplasm.
- FIG 5
Schematic structure of an antibiotic-nanoparticle conjugate reacting with receptors within the cytoplasmic membrane. Ag-NP, silver nanoparticle; ABX, any kind of natural, synthetic, or recombinant antibiotic.
Tables
- TABLE 1
Selection of antimicrobial applications of endolysins and engineered derivativesa
Target pathogen(s) Endolysin(s) and/or derivative(s) Model type (animal[s]) Delivery method(s) Description and/or outcome Reference Streptococcus pyogenes, MRSA PlySs2 In vivo (mouse) Intraperitoneal Protection of 92% of mice from S. pyogenes and MRSA bacteremia 201 Streptococcus suis PlySs2 In vivo (mouse) Intranasal High killing activity against multiple serotypes and strains of S. suis and survival of mice 202 S. pyogenes PlyPy In vivo (mouse) Intraperitoneal Protection of mice from death (90–95%) in a bacteremia model 203 S. pyogenes PlyC In vivo (mouse) Oral, nasal Elimination of the pathogen in orally colonized mice 204 S. aureus CHAPK In vivo (mouse) Intranasal Truncated endolysin construct eliminates S. aureus in the nares of mice 144 Streptococcus agalactiae PlySK1249 In vivo (mouse) Intraperitoneal Protection of 80% of mice from systemic infection 205 S. agalactiae, S. dysgalactiae, S. uberis B30, λSA2 In vivo (mouse) Intramammary Reduction of intramammary bacterial loads (1.5–4.5 logs) in a mouse model of bovine mastitis 127 Streptococcus pneumoniae Cpl-1 In vivo (mouse) Aerosol Reduction in mice mortality due to pneumonia by 80% 206 S. pneumoniae Cpl-1 In vivo (mouse) Intravenous, nasal, oral Reduction of bacterial loads in nasopharyngeal and bacteremia models; longer survival of animals 207 S. pneumoniae Cpl-1 In vivo (mouse) Intraperitoneal Total protection of mice from pneumonia when endolysin was administered within 24 h postinfection; reduced protection with delayed treatment (42% survival) 208 S. pneumoniae Cpl-1 In vivo (rat) Intravenous Elimination of pneumococci causing endocarditis from blood within 30 min with high-dose treatment 209 MRSA PlyGH15 In vivo (mouse) Intraperitoneal Protection of mice from bacteremia 145 MRSA SAL-1 In vivo (mouse) Intravenous Increased survival rate of mice and reduction of bacterial counts in the bloodstream 137 MRSA MV-L In vivo (mouse) Intraperitoneal, nasal Elimination of MRSA from nares of mice and protection against death from systemic infection 125 MRSA 8 different endolysins and lysostaphin In vivo (mouse) Intraperitoneal 100% protection from death by the majority of the tested enzymes; no clinical signs of disease at the end of the treatment 78 B. anthracis PlyG In vivo (mouse) Intraperitoneal Rescue of mice from fatal septicemia 210 MRSA SAL-1 In vivo (rat, dog) Intravenous Absence of adverse effects upon administration of endolysin 146 MRSA ClyH In vivo (mouse) Intraperitoneal 100% protection of mice from death 211 MRSA ClyS In vivo (mouse) Intraperitoneal Protection of mice from death with synergy between the endolysin and oxacillin 121 S. aureus ClyS In vivo (mouse) Topical Better performance (3-log CFU reduction on skin) than that of the antibiotic mupirocin 126 S. aureus λ SA2-E-Lyso-SH3b, λ SA2-E-LysK-SH3b In vivo (mouse) Intramammary Reduction of 3.36 log CFU with combined treatment with lysostaphin in a mouse model of bovine mastitis 101 S. aureus Several chimeric peptidoglycan hydrolases In vivo (mouse, rat) Intranasal, intramammary, intramuscular Better activity than that of the parental protein in models of nasal infection, mastitis, and osteomyelitis 114 S. pneumoniae, S. pyogenes Cpl-7 In vivo (zebrafish embryos) Immersion Increased survival rate of 95–99% of animals; combination with carvacrol was effective at killing Gram-negative bacteria 212 Pseudomonas aeruginosa Artilysin In vivo (Caenorhabditis elegans) Immersion Improved survival of nematodes treated with an artilysin (63%) active against the Gram-negative pathogen compared to the native endolysin (40%) 213 MRSA MR-10 In vivo (mouse) Subcutaneous Combined application with minocycline effectively reduced bacterial burdens in localized and systemic burn wound infections 214 S. aureus PlyGRCS In vivo (mouse) Intravenous PlyGRCS was effective at rescuing 30% of mice from death induced by S. aureus bacteremia after 3.5 days 120 MRSA, MSSA LysGH15 In vivo (mouse) Subcutaneous LysGH15 did not induce resistance in MRSA, and its in vitro and in vivo efficacy was not compromised in the presence of antibodies generated against the endolysin 215 MRSA SAL200 (SAL-1) In vivo (monkey) Intravenous Repeated SAL200 injections over a period of <1 wk or single high-dose injections were well tolerated 138 MRSA SAL200 (SAL-1) In vivo (human) Intravenous Phase 1 clinical study evaluating pharmacokinetics, pharmacodynamics, and tolerance of SAL200 in humans; no serious adverse effects were observed 140 MRSA Trx-SA1 In vivo (cow) Intramammary Significant reductions in pathogen levels and somatic cell counts in milk from udder quarters with mild clinical S. aureus-induced mastitis 216 MSSA, MRSA SA.100 In vivo (human) Topical Case report describing successful treatment of 3 different S. aureus-related dermatoses by topical application of the endolysin-based therapeutic Staphefekt SA.100 217 S. pyogenes PlyC In vitro NA PlyC is able to cross epithelial cell membranes, making it a promising agent to control intracellular streptococci 218 S. suis LySMP In vitro NA Efficacy against biofilms 219 Streptococcus equi PlyC In vitro NA 1,000-fold-higher activity against the causative agent of equine strangles than the commercial disinfectant Virkon-S 220 Streptococcus sp. Ply700 In vitro NA Activity against S. uberis in milk 221 MRSA CHAPK In vitro NA Thermally triggered release of a synergistic staphylolytic cocktail consisting of lysostaphin and CHAPK from poly(N-isopropylacrylamide) nanoparticles 222 E. coli Bacteriophage T5 endolysin In vitro NA Synergistic effect of T5 endolysin in combination with membrane-permeabilizing compounds against Gram-negative bacteria 223 MSSA, MRSA, and ceftaroline-ceftobiprole- and borderline oxacillin-resistant staphylococcal isolates HY-133 In vitro NA Activity of a chimeric endolysin construct against a collection of African staphylococcal strains 133 Multidrug-resistant Acinetobacter baumannii ABgp46 In vitro NA Activity of the novel ABgp46 endolysin against Acinetobacter and other Gram-negative bacteria is enhanced by citric and maleic acids 224 S. aureus, S. epidermidis LysH5 In vitro NA Activity in milk against S. aureus 225 S. aureus LysH5 In vitro NA Expression and secretion of an active staphylococcal endolysin in lactic acid bacteria 157 L. monocytogenes Ply511 In vitro NA Expression and secretion of an active endolysin by lactic acid bacteria 111 A. baumannii LysAB2 In vitro NA LysAB2 exhibited broad bacteriolytic activity against a number of Gram-negative and Gram-positive bacteria 226 S. aureus SAL-2 In vitro NA Activity against planktonic bacteria and biofilms 227 ↵a NA, not applicable.
