Endolysins as Antimicrobials

Nelson, Daniel; Schmelcher, Mathias; Rodríguez-Rubio, Lorena; Klumpp, Jochen; Pritchard, David G.; Dong, Shengli; Donovan, David M.

doi:10.1016/b978-0-12-394438-2.00007-4

Cited by 319 publications

(352 citation statements)

References 208 publications

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“…[5][6][7] These bactericidal proteins could prove particularly powerful, as they act through mechanisms orthogonal to those of conventional antibacterial drugs. Namely, their capacity to catalytically degrade cell wall peptidoglycan underlies a long list of advantages including (1) efficacy against strains resistant to conventional drugs; (2) exquisite specificity for bacteria and minimal off-target effects; (3) efficacy against cells exhibiting low metabolic activity, such as those within biofilms; (4) potential for low effective dosages due to catalytic mechanism of action; and (5) putative reduced rates of resistance development.…”

mentioning

confidence: 99%

Bioengineered lysozyme in combination therapies forPseudomonas aeruginosalung infections

et al. 2014

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confidence: 99%

Bioengineered lysozyme in combination therapies forPseudomonas aeruginosalung infections

et al. 2014

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“…Unlike autolysins, the cell wall binding domain of most phage lysins is found at the C terminus of the molecule (33). Placing such domains at the N terminus of an antibody Fc region (directly replacing the Fab) results in an unnatural orientation for the lysin binding domain, potentially interfering with its function.…”

Section: Resultsmentioning

confidence: 99%

Lysibodies are IgG Fc fusions with lysin binding domains targetingStaphylococcus aureuswall carbohydrates for effective phagocytosis

Raz

Serrano

Lawson

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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The cell wall of Gram-positive bacteria contains abundant surfaceexposed carbohydrate molecules that are highly conserved within and often across species. The potential therapeutic usefulness of high-affinity antibodies to cell wall carbohydrates is unquestioned, however obtaining such antibodies is challenging due to the poor overall immunogenicity of these bacterial targets. Autolysins and phage lysins are peptidoglycan hydrolases, enzymes that have evolved over a billion years to degrade bacterial cell wall. Such wall hydrolases are modular enzymes, composed of discrete domains for high-affinity binding to cell wall carbohydrates and cleavage activity. In this study, we demonstrate that binding domains from autolysins and lysins can be fused to the Fc region of human IgG, creating a fully functional homodimer (or "lysibody") with high-affinity binding and specificity for carbohydrate determinants on the bacterial surface. Furthermore, we demonstrate that this process is reproducible with three different binding domains specific to methicillin-resistant Staphylococcus aureus (MRSA). Cell-bound lysibodies induced the fixation of complement on the bacterial surface, promoted phagocytosis by macrophages and neutrophils, and protected mice from MRSA infection in two model systems. The lysibody approach could be used to target a range of difficult-to-treat pathogenic bacteria, given that cell wall hydrolases are ubiquitous in nature.immunotherapy | antibody | vaccine | monoclonal | peptidoglycan hydrolase

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“…Endolysins have co-evolved with their host strains to degrade the peptidoglycan (PG) cell wall [30][31][32]. Once the cell wall has been compromised, the high internal pressure of bacterial cells causes osmolysis (lysis from within), enabling the release of phage progeny at the end of the phage lytic replication cycle [33].…”

Section: Introductionmentioning

confidence: 99%

“…Once the cell wall has been compromised, the high internal pressure of bacterial cells causes osmolysis (lysis from within), enabling the release of phage progeny at the end of the phage lytic replication cycle [33]. Gram-positive bacteria, which have a thick PG cell wall (up to 40 layers thick) and no outer membrane, can also lyse Gram-positive bacteria when exposed externally to purified endolysins (lysis from without) [30][31][32]. In contrast, the cell walls of Gram-negative bacteria harbor an outer membrane that blocks access of most endolysins to the PG located in the periplasmic space.…”

Section: Introductionmentioning

confidence: 99%

“…Endolysins have a modular structure, usually composed of N-terminal catalytic domain(s) (that is, endopeptidase, glycosidase, and amidases) and a C-terminal cell wall binding domain (CBD) [36,37]. Endolysins show near-species specificity and are highly refractory to resistance development [30][31][32], likely due to their co-evolution with their host, and because of the need to target highly immutable PG structures in order to ensure phage escape from the host cell and the clade survival. Further decreasing the risk of resistance development to endolysins is the localization of the Gram-positive PG layer outside the cytoplasmic membrane, since most antibiotic resistance mechanisms act on compounds that localize intracellularly (for example, efflux pumps; see [38] for a review).…”

Section: Introductionmentioning

confidence: 99%

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Saccharomyces cerevisiae expressing bacteriophage endolysins reduce Lactobacillus contamination during fermentation

Khatibi

Roach

Donovan

et al. 2014

Biotechnol Biofuels

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Background: One of the challenges facing the fuel ethanol industry is the management of bacterial contamination during fermentation. Lactobacillus species are the predominant contaminants that decrease the profitability of biofuel production by reducing ethanol yields and causing "stuck" fermentations, which incur additional economic losses via expensive antibiotic treatments and disinfection costs. The current use of antibiotic treatments has led to the emergence of drug-resistant bacterial strains, and antibiotic residues in distillers dried grains with solubles (DDGS) are a concern for the feed and food industries. This underscores the need for new, non-antibiotic, eco-friendly mitigation strategies for bacterial contamination. The specific objectives of this work were to (1) express genes encoding bacteriophage lytic enzymes (endolysins) in Saccharomyces cerevisiae, (2) assess the lytic activity of the yeast-expressed enzymes against different species of Lactobacillus that commonly contaminate fuel ethanol fermentations, and (3) test the ability of yeast expressing lytic enzymes to reduce Lactobacillus fermentum during fermentation. Implementing antibiotic-free strategies to reduce fermentation contaminants will enable more cost-effective fuel ethanol production and will impact both producers and consumers in the farm-to-fork continuum. Results: Two genes encoding the lytic enzymes LysA and LysA2 were individually expressed in S. cerevisiae on multi-copy plasmids under the control of a galactose-inducible promoter. The enzymes purified from yeast were lytic against Lactobacillus isolates collected from fermentors at a commercial dry grind ethanol facility including Lactobacillus fermentum, Lactobacillus brevis, and Lactobacillus mucosae. Reductions of L. fermentum in experimentally infected fermentations with yeast expressing LysA or LysA2 ranged from 0.5 log 10 colony-forming units per mL (CFU/mL) to 1.8 log 10 (CFU/mL) over 72 h and fermentations treated with transformed yeast lysate showed reductions that ranged from 0.9 log 10 (CFU/mL) to 3.3 log 10 (CFU/mL). Likewise, lactic acid and acetic acid levels were reduced in all experimentally infected fermentations containing transformed yeast (harboring endolysin expressing plasmids) relative to the corresponding fermentations with untransformed yeast.

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Endolysins as Antimicrobials

Cited by 319 publications

References 208 publications

Bioengineered lysozyme in combination therapies forPseudomonas aeruginosalung infections

Bioengineered lysozyme in combination therapies forPseudomonas aeruginosalung infections

Lysibodies are IgG Fc fusions with lysin binding domains targetingStaphylococcus aureuswall carbohydrates for effective phagocytosis

Saccharomyces cerevisiae expressing bacteriophage endolysins reduce Lactobacillus contamination during fermentation

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