Viruses

Editorial

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3 pages, 167 KiB

Open AccessEditorial

Phage Lytic Enzymes

by Yves Briers

Viruses 2019, 11(2), 113; https://doi.org/10.3390/v11020113 - 29 Jan 2019

Cited by 16 | Viewed by 4474

Abstract

Phage lytic enzymes are enzymes produced by bacterial viruses, either as part of their virion to facilitate bacterial infection through local peptidoglycan degradation, or as soluble proteins to induce massive cell lysis at the end of the lytic replication cycle [...] Full article

(This article belongs to the Special Issue Phage Lytic Enzymes and Their Applications)

Research

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17 pages, 2379 KiB

Open AccessArticle

Synergistic Removal of Static and Dynamic Staphylococcus aureus Biofilms by Combined Treatment with a Bacteriophage Endolysin and a Polysaccharide Depolymerase

by Nanna M. C. Olsen, Elowine Thiran, Tobias Hasler, Thomas Vanzieleghem, Georgios N. Belibasakis, Jacques Mahillon, Martin J. Loessner and Mathias Schmelcher

Viruses 2018, 10(8), 438; https://doi.org/10.3390/v10080438 - 18 Aug 2018

Cited by 64 | Viewed by 7800

Abstract

Staphylococcus aureus is an important pathogen and biofilm former. Biofilms cause problems in clinics and food production and are highly recalcitrant to antibiotics and sanitizers. Bacteriophage endolysins kill bacteria by degrading their cell wall and are therefore deemed promising antimicrobials and anti-biofilm agents. [...] Read more.

Staphylococcus aureus is an important pathogen and biofilm former. Biofilms cause problems in clinics and food production and are highly recalcitrant to antibiotics and sanitizers. Bacteriophage endolysins kill bacteria by degrading their cell wall and are therefore deemed promising antimicrobials and anti-biofilm agents. Depolymerases targeting polysaccharides in the extracellular matrix have been suggested as parts of a multi-enzyme approach to eradicate biofilms. The efficacy of endolysins and depolymerases against S. aureus biofilms in static models has been demonstrated. However, there is a lack of studies evaluating their activity against biofilms grown under more realistic conditions. Here, we investigated the efficacy of the endolysin LysK and the poly-N-acetylglucosamine depolymerase DA7 against staphylococcal biofilms in static and dynamic (flow cell-based) models. LysK showed activity against multiple S. aureus strains, and both LysK and DA7 removed static and dynamic biofilms from polystyrene and glass surfaces at low micromolar and nanomolar concentrations, respectively. When combined, the enzymes acted synergistically, as demonstrated by crystal violet staining of static biofilms, significantly reducing viable cell counts compared to individual enzyme treatment in the dynamic model, and confocal laser scanning microscopy. Overall, our results suggest that LysK and DA7 are potent anti-biofilm agents, alone and in combination. Full article

(This article belongs to the Special Issue Phage Lytic Enzymes and Their Applications)

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13 pages, 2561 KiB

Open AccessArticle

Activity of the Chimeric Lysin ClyR against Common Gram-Positive Oral Microbes and Its Anticaries Efficacy in Rat Models

by Jingjing Xu, Hang Yang, Yongli Bi, Wuyou Li, Hongping Wei and Yuhong Li

Viruses 2018, 10(7), 380; https://doi.org/10.3390/v10070380 - 20 Jul 2018

Cited by 22 | Viewed by 5229

Abstract

Dental caries is a common disease caused by oral bacteria. Streptococcus mutans and Streptococcus sobrinus are the primary cariogenic microbes that often survive as biofilms on teeth. In this study, we evaluated the activity of ClyR, a well-known chimeric lysin with extended streptococcal [...] Read more.

Dental caries is a common disease caused by oral bacteria. Streptococcus mutans and Streptococcus sobrinus are the primary cariogenic microbes that often survive as biofilms on teeth. In this study, we evaluated the activity of ClyR, a well-known chimeric lysin with extended streptococcal host range, against common Gram-positive oral microbes and its anticaries efficacy in rat models. ClyR demonstrated high lytic activity against S. mutans MT8148 and S. sobrinus ATCC6715, with minor activity against Streptococcus sanguinis, Streptococcus oralis, and Streptococcus salivarius, which are considered as harmless commensal oral bacteria. Confocal laser scanning microscopy showed that the number of viable cells in 72-h aged S. mutans and S. sobrinus biofilms are significantly (p < 0.05) decreased after treatment with 50 µg/mL ClyR for 5 min. Furthermore, continuous administration of ClyR for 40 days (5 µg/day) significantly (p < 0.05) reduced the severity of caries in rat models infected with a single or a mixed bacteria of S. mutans and S. sobrinus. Therefore, ClyR could be a promising agent or additive for the prevention and treatment of dental caries. Full article

(This article belongs to the Special Issue Phage Lytic Enzymes and Their Applications)

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13 pages, 2065 KiB

Open AccessArticle

Structure of an Acinetobacter Broad-Range Prophage Endolysin Reveals a C-Terminal α-Helix with the Proposed Role in Activity against Live Bacterial Cells

by Nina N. Sykilinda, Alena Y. Nikolaeva, Mikhail M. Shneider, Dmitry V. Mishkin, Artem A. Patutin, Vladimir O. Popov, Konstantin M. Boyko, Natalia L. Klyachko and Konstantin A. Miroshnikov

Viruses 2018, 10(6), 309; https://doi.org/10.3390/v10060309 - 6 Jun 2018

Cited by 26 | Viewed by 4825

Abstract

Proteins that include enzymatic domain degrading the bacterial cell wall and a domain providing transport through the bacterial outer membrane are considered as prospective compounds to combat pathogenic Gram-negative bacteria. This paper presents an isolation and study of an enzyme of this class [...] Read more.

Proteins that include enzymatic domain degrading the bacterial cell wall and a domain providing transport through the bacterial outer membrane are considered as prospective compounds to combat pathogenic Gram-negative bacteria. This paper presents an isolation and study of an enzyme of this class naturally encoded in the prophage region of Acinetobacter baumannii AB 5075 genome. Recombinant protein expressed in E. coli exhibits an antimicrobial activity with respect to live cultures of Gram-negative bacteria reducing the population of viable bacteria by 1.5–2 log colony forming units (CFU)/mL. However the protein becomes rapidly inactivated and enables the bacteria to restore the population. AcLys structure determined by X-ray crystallography reveals a predominantly α—helical fold similar to bacteriophage P22 lysozyme. The С-terminal part of AcLys polypeptide chains forms an α—helix enriched by Lys and Arg residues exposed outside of the protein globule. Presumably this type of structure of the C-terminal α—helix has evolved evolutionally enabling the endolysin to pass the inner membrane during the host lysis or, potentially, to penetrate the outer membrane of the Gram-negative bacteria. Full article

(This article belongs to the Special Issue Phage Lytic Enzymes and Their Applications)

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13 pages, 3357 KiB

Open AccessArticle

Effects of a Chimeric Lysin against Planktonic and Sessile Enterococcus faecalis Hint at Potential Application in Endodontic Therapy

by Wuyou Li, Hang Yang, Yujing Gong, Shujuan Wang, Yuhong Li and Hongping Wei

Viruses 2018, 10(6), 290; https://doi.org/10.3390/v10060290 - 29 May 2018

Cited by 14 | Viewed by 4244

Abstract

Enterococcus faecalis is a commensal opportunistic pathogen found in the intestine, mouth, and vaginal tract of humans. As an invasive pathogen in the oral cavity, E. faecalis is one of the leading causes of periapical endodontic lesions. However, due to the strong biofilm-forming [...] Read more.

Enterococcus faecalis is a commensal opportunistic pathogen found in the intestine, mouth, and vaginal tract of humans. As an invasive pathogen in the oral cavity, E. faecalis is one of the leading causes of periapical endodontic lesions. However, due to the strong biofilm-forming capacity and tolerance of E. faecalis to conventional antibiotics and treatments, limited therapeutic options are available. In the present study, we investigated the activity of ClyR, a chimeric lysin with extended streptococcal lytic spectrum, against planktonic and sessile E. faecalis cells in vitro and in an ex vivo dental model. Our results showed that ClyR has robust and rapid lytic activity against multiple E. faecalis strains, killing >90% planktonic cells within 1 min at a concentration of 50 μg/mL. The biochemical experiments combined with microscopy analysis revealed that ClyR degrades E. faecalis biofilm with high efficacy in a dose-dependent manner, reducing the survival rate to <40% within biofilms after treatment with 50 μg/mL ClyR for 1 h. In the ex vivo dental model, ClyR showed a significant biofilm removal efficacy, killing >90% viable bacteria within biofilms at a low dose of 50 μg/mL, which is much better than ampicillin and similar to calcium hydroxide, the extensively used routine intracanal medicament in the treatment of endodontics and dental traumatology. The robust activity of ClyR against both planktonic and sessile E. faecalis suggests the potential of ClyR in treating endodontic infections caused by E. faecalis. Full article

(This article belongs to the Special Issue Phage Lytic Enzymes and Their Applications)

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12 pages, 3294 KiB

Open AccessArticle

The Auxiliary Role of the Amidase Domain in Cell Wall Binding and Exolytic Activity of Staphylococcal Phage Endolysins

by Bokyung Son, Minsuk Kong and Sangryeol Ryu

Viruses 2018, 10(6), 284; https://doi.org/10.3390/v10060284 - 25 May 2018

Cited by 30 | Viewed by 4364

Abstract

In response to increasing concern over antibiotic-resistant Staphylococcus aureus, the development of novel antimicrobials has been called for, with bacteriophage endolysins having received considerable attention as alternatives to antibiotics. Most staphylococcal phage endolysins have a modular structure consisting of an N-terminal cysteine, [...] Read more.

In response to increasing concern over antibiotic-resistant Staphylococcus aureus, the development of novel antimicrobials has been called for, with bacteriophage endolysins having received considerable attention as alternatives to antibiotics. Most staphylococcal phage endolysins have a modular structure consisting of an N-terminal cysteine, histidine-dependent amidohydrolases/peptidase domain (CHAP), a central amidase domain, and a C-terminal cell wall binding domain (CBD). Despite extensive studies using truncated staphylococcal endolysins, the precise function of the amidase domain has not been determined. Here, a functional analysis of each domain of two S. aureus phage endolysins (LysSA12 and LysSA97) revealed that the CHAP domain conferred the main catalytic activity, while the central amidase domain showed no enzymatic activity in degrading the intact S. aureus cell wall. However, the amidase-lacking endolysins had reduced hydrolytic activity compared to the full-length endolysins. Comparison of the binding affinities of fusion proteins consisting of the green fluorescent protein (GFP) with CBD and GFP with the amidase domain and CBD revealed that the major function of the amidase domain was to enhance the binding affinity of CBD, resulting in higher lytic activity of endolysin. These results suggest an auxiliary binding role of the amidase domain of staphylococcal endolysins, which can be useful information for designing effective antimicrobial and diagnostic agents against S. aureus. Full article

(This article belongs to the Special Issue Phage Lytic Enzymes and Their Applications)

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16 pages, 1056 KiB

Open AccessArticle

Yeast Derived LysA2 Can Control Bacterial Contamination in Ethanol Fermentation

by Jun-Seob Kim, M. Angela Daum, Yong-Su Jin and Michael J. Miller

Viruses 2018, 10(6), 281; https://doi.org/10.3390/v10060281 - 24 May 2018

Cited by 13 | Viewed by 4779

Abstract

Contamination of fuel-ethanol fermentations continues to be a significant problem for the corn and sugarcane-based ethanol industries. In particular, members of the Lactobacillaceae family are the primary bacteria of concern. Currently, antibiotics and acid washing are two major means of controlling contaminants. However, [...] Read more.

Contamination of fuel-ethanol fermentations continues to be a significant problem for the corn and sugarcane-based ethanol industries. In particular, members of the Lactobacillaceae family are the primary bacteria of concern. Currently, antibiotics and acid washing are two major means of controlling contaminants. However, antibiotic use could lead to increased antibiotic resistance, and the acid wash step stresses the fermenting yeast and has limited effectiveness. Bacteriophage endolysins such as LysA2 are lytic enzymes with the potential to contribute as antimicrobials to the fuel ethanol industries. Our goal was to evaluate the potential of yeast-derived LysA2 as a means of controlling Lactobacillaceae contamination. LysA2 intracellularly produced by Pichia pastoris showed activity comparable to Escherichia coli produced LysA2. Lactic Acid Bacteria (LAB) with the A4α peptidoglycan chemotype (L-Lys-D-Asp crosslinkage) were the most sensitive to LysA2, though a few from that chemotype were insensitive. Pichia-expressed LysA2, both secreted and intracellularly produced, successfully improved ethanol productivity and yields in glucose (YPD60) and sucrose-based (sugarcane juice) ethanol fermentations in the presence of a LysA2 susceptible LAB contaminant. LysA2 secreting Sacharomyces cerevisiae did not notably improve production in sugarcane juice, but it did control bacterial contamination during fermentation in YPD60. Secretion of LysA2 by the fermenting yeast, or adding it in purified form, are promising alternative tools to control LAB contamination during ethanol fermentation. Endolysins with much broader lytic spectrums than LysA2 could supplement or replace the currently used antibiotics or the acidic wash. Full article

(This article belongs to the Special Issue Phage Lytic Enzymes and Their Applications)

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19 pages, 2836 KiB

Open AccessArticle

Discovery and Biochemical Characterization of PlyP56, PlyN74, and PlyTB40—Bacillus Specific Endolysins

by Irina Etobayeva, Sara B. Linden, Farhang Alem, Laith Harb, Lucas Rizkalla, Philip D. Mosier, Allison A. Johnson, Louise Temple, Ramin M. Hakami and Daniel C. Nelson

Viruses 2018, 10(5), 276; https://doi.org/10.3390/v10050276 - 21 May 2018

Cited by 25 | Viewed by 5518

Abstract

Three Bacillus bacteriophage-derived endolysins, designated PlyP56, PlyN74, and PlyTB40, were identified, cloned, purified, and characterized for their antimicrobial properties. Sequence alignment reveals these endolysins have an N-terminal enzymatically active domain (EAD) linked to a C-terminal cell wall binding domain (CBD). PlyP56 has a [...] Read more.

Three Bacillus bacteriophage-derived endolysins, designated PlyP56, PlyN74, and PlyTB40, were identified, cloned, purified, and characterized for their antimicrobial properties. Sequence alignment reveals these endolysins have an N-terminal enzymatically active domain (EAD) linked to a C-terminal cell wall binding domain (CBD). PlyP56 has a Peptidase_M15_4/VanY superfamily EAD with a conserved metal binding motif and displays biological dependence on divalent ions for activity. In contrast, PlyN74 and PlyTB40 have T7 lysozyme-type Amidase_2 and carboxypeptidase T-type Amidase_3 EADs, respectively, which are members of the MurNAc-LAA superfamily, but are not homologs and thus do not have a shared protein fold. All three endolysins contain similar SH3-family CBDs. Although minor host range differences were noted, all three endolysins show relatively broad antimicrobial activity against members of the Bacillus cereus sensu lato group with the highest lytic activity against B. cereus ATCC 4342. Characterization studies determined the optimal lytic activity for these enzymes was at physiological pH (pH 7.0–8.0), over a broad temperature range (4–55 °C), and at low concentrations of NaCl (<50 mM). Direct comparison of lytic activity shows the PlyP56 enzyme to be twice as effective at lysing the cell wall peptidoglycan as PlyN74 or PlyTB40, suggesting PlyP56 is a good candidate for further antimicrobial development as well as bioengineering studies. Full article

(This article belongs to the Special Issue Phage Lytic Enzymes and Their Applications)

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15 pages, 4129 KiB

Open AccessArticle

An Ointment Consisting of the Phage Lysin LysGH15 and Apigenin for Decolonization of Methicillin-Resistant Staphylococcus aureus from Skin Wounds

by Mengjun Cheng, Lei Zhang, Hao Zhang, Xinwei Li, Yanmei Wang, Feifei Xia, Bin Wang, Ruopeng Cai, Zhimin Guo, Yufeng Zhang, Yalu Ji, Changjiang Sun, Xin Feng, Liancheng Lei, Yongjun Yang, Wenyu Han and Jingmin Gu

Viruses 2018, 10(5), 244; https://doi.org/10.3390/v10050244 - 6 May 2018

Cited by 42 | Viewed by 5909

Abstract

Staphylococcus aureus (S. aureus) is a common and dangerous pathogen that causes various infectious diseases. Skin damage, such as burn wounds, are at high risk of Staphylococcus aureus colonization and infection, which increases morbidity and mortality. The phage lysin LysGH15 exhibits [...] Read more.

Staphylococcus aureus (S. aureus) is a common and dangerous pathogen that causes various infectious diseases. Skin damage, such as burn wounds, are at high risk of Staphylococcus aureus colonization and infection, which increases morbidity and mortality. The phage lysin LysGH15 exhibits highly efficient lytic activity against methicillin-resistant S. aureus (MRSA) and methicillin-susceptible S. aureus (MSSA) strains. Apigenin (api) significantly decreases haemolysis of rabbit erythrocytes caused by S. aureus and shows anti-inflammatory function. LysGH15 and api were added to Aquaphor to form an LysGH15-api-Aquaphor (LAA) ointment. The LAA ointment simultaneously exhibited bactericidal activity against S. aureus and inhibited haemolysis. In an LAA-treated mouse model of an MRSA-infected skin wound, the mean bacterial colony count decreased to approximately 10² CFU/mg at 18 h after treatment (and the bacteria became undetectable at 96 h), whereas the mean count in untreated mice was approximately 10⁵ CFU/mg of tissue. The LAA ointment also reduced the levels of pro-inflammatory cytokines (TNF-α, IL-1β, and IFN-γ) and accelerated wound healing in the mouse model. These data demonstrate the potential efficacy of a combination of LysGH15 and api for use as a topical antimicrobial agent against S. aureus. Full article

(This article belongs to the Special Issue Phage Lytic Enzymes and Their Applications)

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16 pages, 7642 KiB

Open AccessArticle

Characterization of a New Staphylococcus aureus Kayvirus Harboring a Lysin Active against Biofilms

by Luís D. R. Melo, Ana Brandão, Ergun Akturk, Silvio B. Santos and Joana Azeredo

Viruses 2018, 10(4), 182; https://doi.org/10.3390/v10040182 - 7 Apr 2018

Cited by 50 | Viewed by 7460

Abstract

Staphylococcus aureus is one of the most relevant opportunistic pathogens involved in many biofilm-associated diseases, and is a major cause of nosocomial infections, mainly due to the increasing prevalence of multidrug-resistant strains. Consequently, alternative methods to eradicate the pathogen are urgent. It has [...] Read more.

Staphylococcus aureus is one of the most relevant opportunistic pathogens involved in many biofilm-associated diseases, and is a major cause of nosocomial infections, mainly due to the increasing prevalence of multidrug-resistant strains. Consequently, alternative methods to eradicate the pathogen are urgent. It has been previously shown that polyvalent staphylococcal kayviruses and their derived endolysins are excellent candidates for therapy. Here we present the characterization of a new bacteriophage: vB_SauM-LM12 (LM12). LM12 has a broad host range (>90%; 56 strains tested), and is active against several MRSA strains. The genome of LM12 is composed of a dsDNA molecule with 143,625 bp, with average GC content of 30.25% and codes for 227 Coding Sequences (CDSs). Bioinformatics analysis did not identify any gene encoding virulence factors, toxins, or antibiotic resistance determinants. Antibiofilm assays have shown that this phage significantly reduced the number of viable cells (less than one order of magnitude). Moreover, the encoded endolysin also showed activity against biofilms, with a consistent biomass reduction during prolonged periods of treatment (of about one order of magnitude). Interestingly, the endolysin was shown to be much more active against stationary-phase cells and suspended biofilm cells than against intact and scraped biofilms, suggesting that cellular aggregates protected by the biofilm matrix reduced protein activity. Both phage LM12 and its endolysin seem to have a strong antimicrobial effect and broad host range against S. aureus, suggesting their potential to treat S. aureus biofilm infections. Full article

(This article belongs to the Special Issue Phage Lytic Enzymes and Their Applications)

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Review

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16 pages, 255 KiB

Open AccessReview

The Preclinical and Clinical Progress of Bacteriophages and Their Lytic Enzymes: The Parts are Easier than the Whole

by Karim Abdelkader, Hans Gerstmans, Amal Saafan, Tarek Dishisha and Yves Briers

Viruses 2019, 11(2), 96; https://doi.org/10.3390/v11020096 - 24 Jan 2019

Cited by 121 | Viewed by 9349

Abstract

The therapeutic potential of phages has been considered since their first identification more than a century ago. The evident concept of using a natural predator to treat bacterial infections has, however, since then been challenged considerably. Initially, the vast success of antibiotics almost [...] Read more.

The therapeutic potential of phages has been considered since their first identification more than a century ago. The evident concept of using a natural predator to treat bacterial infections has, however, since then been challenged considerably. Initially, the vast success of antibiotics almost eliminated the study of phages for therapy. Upon the renaissance of phage therapy research, the most provocative and unique properties of phages such as high specificity, self-replication and co-evolution prohibited a rapid preclinical and clinical development. On the one hand, the typical trajectory followed by small molecule antibiotics could not be simply translated into the preclinical analysis of phages, exemplified by the need for complex broad spectrum or personalized phage cocktails of high purity and the more complex pharmacokinetics. On the other hand, there was no fitting regulatory framework to deal with flexible and sustainable phage therapy approaches, including the setup and approval of adequate clinical trials. While significant advances are incrementally made to eliminate these hurdles, phage-inspired antibacterials have progressed in the slipstream of phage therapy, benefiting from the lack of hurdles that are typically associated with phage therapy. Most advanced are phage lytic enzymes that kill bacteria through peptidoglycan degradation and osmotic lysis. Both phages and their lytic enzymes are now widely considered as safe and have now progressed to clinical phase II to show clinical efficacy as pharmaceutical. Yet, more initiatives are needed to fill the clinical pipeline to beat the typical attrition rates of clinical evaluation and to come to a true evaluation of phages and phage lytic enzymes in the clinic. Full article

(This article belongs to the Special Issue Phage Lytic Enzymes and Their Applications)

18 pages, 750 KiB

Open AccessReview

Mycobacteriophage Lysis Enzymes: Targeting the Mycobacterial Cell Envelope

by Maria João Catalão and Madalena Pimentel

Viruses 2018, 10(8), 428; https://doi.org/10.3390/v10080428 - 14 Aug 2018

Cited by 43 | Viewed by 7900

Abstract

Mycobacteriophages are viruses that specifically infect mycobacteria, which ultimately culminate in host cell death. Dedicated enzymes targeting the complex mycobacterial cell envelope arrangement have been identified in mycobacteriophage genomes, thus being potential candidates as antibacterial agents. These comprise lipolytic enzymes that target the [...] Read more.

Mycobacteriophages are viruses that specifically infect mycobacteria, which ultimately culminate in host cell death. Dedicated enzymes targeting the complex mycobacterial cell envelope arrangement have been identified in mycobacteriophage genomes, thus being potential candidates as antibacterial agents. These comprise lipolytic enzymes that target the mycolic acid-containing outer membrane and peptidoglycan hydrolases responsive to the atypical mycobacterial peptidoglycan layer. In the recent years, a remarkable progress has been made, particularly on the comprehension of the mechanisms of bacteriophage lysis proteins activity and regulation. Notwithstanding, information about mycobacteriophages lysis strategies is limited and is mainly represented by the studies performed with mycobacteriophage Ms6. Since mycobacteriophages target a specific group of bacteria, which include Mycobacterium tuberculosis responsible for one of the leading causes of death worldwide, exploitation of the use of these lytic enzymes demands a special attention, as they may be an alternative to tackle multidrug resistant tuberculosis. This review focuses on the current knowledge of the function of lysis proteins encoded by mycobacteriophages and their potential applications, which may contribute to increasing the effectiveness of antimycobacterial therapy. Full article

(This article belongs to the Special Issue Phage Lytic Enzymes and Their Applications)

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22 pages, 2046 KiB

Open AccessReview

Enzymes and Mechanisms Employed by Tailed Bacteriophages to Breach the Bacterial Cell Barriers

by Sofia Fernandes and Carlos São-José

Viruses 2018, 10(8), 396; https://doi.org/10.3390/v10080396 - 27 Jul 2018

Cited by 115 | Viewed by 10286

Abstract

Monoderm bacteria possess a cell envelope made of a cytoplasmic membrane and a cell wall, whereas diderm bacteria have and extra lipid layer, the outer membrane, covering the cell wall. Both cell types can also produce extracellular protective coats composed of polymeric substances [...] Read more.

Monoderm bacteria possess a cell envelope made of a cytoplasmic membrane and a cell wall, whereas diderm bacteria have and extra lipid layer, the outer membrane, covering the cell wall. Both cell types can also produce extracellular protective coats composed of polymeric substances like, for example, polysaccharidic capsules. Many of these structures form a tight physical barrier impenetrable by phage virus particles. Tailed phages evolved strategies/functions to overcome the different layers of the bacterial cell envelope, first to deliver the genetic material to the host cell cytoplasm for virus multiplication, and then to release the virion offspring at the end of the reproductive cycle. There is however a major difference between these two crucial steps of the phage infection cycle: virus entry cannot compromise cell viability, whereas effective virion progeny release requires host cell lysis. Here we present an overview of the viral structures, key protein players and mechanisms underlying phage DNA entry to bacteria, and then escape of the newly-formed virus particles from infected hosts. Understanding the biological context and mode of action of the phage-derived enzymes that compromise the bacterial cell envelope may provide valuable information for their application as antimicrobials. Full article

(This article belongs to the Special Issue Phage Lytic Enzymes and Their Applications)

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18 pages, 813 KiB

Open AccessReview

Phage-Derived Peptidoglycan Degrading Enzymes: Challenges and Future Prospects for In Vivo Therapy

by Hugo Oliveira, Carlos São-José and Joana Azeredo

Viruses 2018, 10(6), 292; https://doi.org/10.3390/v10060292 - 29 May 2018

Cited by 111 | Viewed by 8513

Abstract

Peptidoglycan degrading enzymes are of increasing interest as antibacterial agents, especially against multi-drug resistant pathogens. Herein we present a review about the biological features of virion-associated lysins and endolysins, phage-derived enzymes that have naturally evolved to compromise the bacterial peptidoglycan from without and [...] Read more.

Peptidoglycan degrading enzymes are of increasing interest as antibacterial agents, especially against multi-drug resistant pathogens. Herein we present a review about the biological features of virion-associated lysins and endolysins, phage-derived enzymes that have naturally evolved to compromise the bacterial peptidoglycan from without and from within, respectively. These natural features may determine the adaptability of the enzymes to kill bacteria in different environments. Endolysins are by far the most studied group of peptidoglycan-degrading enzymes, with several studies showing that they can exhibit potent antibacterial activity under specific conditions. However, the lytic activity of most endolysins seems to be significantly reduced when tested against actively growing bacteria, something that may be related to fact that these enzymes are naturally designed to degrade the peptidoglycan from within dead cells. This may negatively impact the efficacy of the endolysin in treating some infections in vivo. Here, we present a critical view of the methods commonly used to evaluate in vitro and in vivo the antibacterial performance of PG-degrading enzymes, focusing on the major hurdles concerning in vitro-to-in vivo translation. Full article

(This article belongs to the Special Issue Phage Lytic Enzymes and Their Applications)

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Other

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10 pages, 3985 KiB

Open AccessEssay

Development of Phage Lysins as Novel Therapeutics: A Historical Perspective

by Vincent A. Fischetti

Viruses 2018, 10(6), 310; https://doi.org/10.3390/v10060310 - 7 Jun 2018

Cited by 121 | Viewed by 9859

Abstract

Bacteriophage lysins and related bacteriolytic enzymes are now considered among the top antibiotic alternatives for solving the mounting resistance problem. Over the past 17 years, lysins have been widely developed against Gram-positive and recently Gram-negative pathogens, and successfully tested in a variety of [...] Read more.

Bacteriophage lysins and related bacteriolytic enzymes are now considered among the top antibiotic alternatives for solving the mounting resistance problem. Over the past 17 years, lysins have been widely developed against Gram-positive and recently Gram-negative pathogens, and successfully tested in a variety of animal models to demonstrate their efficacy. A lysin (CF-301) directed to methicillin resistant Staphylococcus aureus (MRSA) has effectively completed phase 1 human clinical trials, showing safety in this novel therapeutic class. To validate efficacy, CF-301 is currently the first lysin to enter phase 2 human trials to treat hospitalized patients with MRSA bacteremia or endocarditis. If successful, it could be the defining moment leading to the acceptance of lysins as an alternative to small molecule antibiotics. This article is a detailed account of events leading to the first therapeutic use and ultimate development of phage-encoded lysins as novel anti-infectives. Full article

(This article belongs to the Special Issue Phage Lytic Enzymes and Their Applications)

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