Development of a Novel Chimeric Endolysin, Lys109 With Enhanced Lytic Activity Against Staphylococcus aureus

Son, Bo‐Kyung; Kong, Minsuk; Lee, Yoona; Ryu, Sangryeol

doi:10.3389/fmicb.2020.615887

Cited by 34 publications

(34 citation statements)

References 58 publications

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“…Previous reports have shown that endolysin added from the outside results in cell death, which may be due to two reasons. One is that endolysin can directly attack the molecular structure of Gram-positive bacteria, which have no outer membrane [56,57]. The other is that endolysins with antibacterial effects in vitro are generally applied to bacteria together with outer membrane permeabilizers [58][59][60], as Gram-negative bacteria have an outer membrane, preventing antibacterial effects [54].…”

Section: Purified X2-lys Shows Antibacterial Activitymentioning

confidence: 99%

The Holin-Endolysin Lysis System of the OP2-Like Phage X2 Infecting Xanthomonas oryzae pv. oryzae

Zhang

et al. 2021

Viruses

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Most endolysins of dsDNA phages are exported by a holin-dependent mechanism, while in some cases endolysins are exported via a holin-independent mechanism. However, it is still unclear whether the same endolysins can be exported by both holin-dependent and holin-independent mechanisms. This study investigated the lysis system of OP2-like phage X2 infecting Xanthomonas oryzae pv. oryzae, causing devastating bacterial leaf blight disease in rice. Based on bioinformatics and protein biochemistry methods, we show that phage X2 employs the classic "holin-endolysin" lysis system. The endolysin acts on the cell envelope and exhibits antibacterial effects in vitro, while the holin facilitates the release of the protein into the periplasm. We also characterized the role of the transmembrane domain (TMD) in the translocation of the endolysin across the inner membrane. We found that the TMD facilitated the translocation of the endolysin via the Sec secretion system. The holin increases the efficiency of protein release, leading to faster and more efficient lysis. Interestingly, in E. coli, the expression of either holin or endolysin with TMDs resulted in the formation of long rod shaped cells. We conclude that the TMD of X2-Lys plays a dual role: One is the transmembrane transport while the other is the inhibition of cell division, resulting in larger cells and thus in a higher number of released viruses per cell.

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Section: Purified X2-lys Shows Antibacterial Activitymentioning

confidence: 99%

The Holin-Endolysin Lysis System of the OP2-Like Phage X2 Infecting Xanthomonas oryzae pv. oryzae

Zhang

et al. 2021

Viruses

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“…PGHs have become extensively studied for 20 years, e.g., [ 11 , 15 , 17 , 53 , 54 , 59 , 61 , 63 , 64 , 65 , 67 , 69 , 82 , 106 , 141 , 142 , 143 , 144 , 148 , 157 , 158 , 159 , 160 , 161 , 162 , 163 , 164 , 165 , 166 , 167 , 168 , 169 , 170 , 171 , 172 , 173 , 174 , 175 , 176 , 177 , 178 , 179 , 180 , 181 , 182 , 183 , 184 , 185 , 186 , 187 , 188 ,…”

Section: Phage-encoded Peptidoglycan Hydrolases (Pghs)mentioning

confidence: 99%

“…Examples of pathogens against which they have been developed include Bacillus anthracis [ 180 ], Clostridium spp. [ 178 , 244 ], Enterococcus faecium [ 183 ], P. aeruginosa [ 205 ], S. aureus [ 186 ], S. epidermidis [ 188 , 245 ], S. pneumoniae [ 185 ], K. pneumoniae [ 184 ], and many others [ 27 ]. They can be used to treat biofilms [ 164 , 188 , 205 , 246 , 247 , 248 , 249 , 250 ], can be applied to mucosal surfaces [ 251 ], and are active against persister cells [ 188 , 252 , 253 ].…”

Section: Phage-encoded Peptidoglycan Hydrolases (Pghs)mentioning

confidence: 99%

Treating Bacterial Infections with Bacteriophage-Based Enzybiotics: In Vitro, In Vivo and Clinical Application

2021

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Over the past few decades, we have witnessed a surge around the world in the emergence of antibiotic-resistant bacteria. This global health threat arose mainly due to the overuse and misuse of antibiotics as well as a relative lack of new drug classes in development pipelines. Innovative antibacterial therapeutics and strategies are, therefore, in grave need. For the last twenty years, antimicrobial enzymes encoded by bacteriophages, viruses that can lyse and kill bacteria, have gained tremendous interest. There are two classes of these phage-derived enzymes, referred to also as enzybiotics: peptidoglycan hydrolases (lysins), which degrade the bacterial peptidoglycan layer, and polysaccharide depolymerases, which target extracellular or surface polysaccharides, i.e., bacterial capsules, slime layers, biofilm matrix, or lipopolysaccharides. Their features include distinctive modes of action, high efficiency, pathogen specificity, diversity in structure and activity, low possibility of bacterial resistance development, and no observed cross-resistance with currently used antibiotics. Additionally, and unlike antibiotics, enzybiotics can target metabolically inactive persister cells. These phage-derived enzymes have been tested in various animal models to combat both Gram-positive and Gram-negative bacteria, and in recent years peptidoglycan hydrolases have entered clinical trials. Here, we review the testing and clinical use of these enzymes.

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“…Crystal violet staining was used to examine the biofilm-inhibitory activity of the lysin, which reduced S. aureus CCARM 3090 and S. aureus RN4220 biofilms by 3-fold compared to its parental lysin SA012. At a concentration of 1000 nM Lys109 reduced the OD570 of the S. aureus CCARM 3090 and S. aureus RN4220 biofilms from 1 (control) to <0.2 in both cases ( Son et al, 2021 ). CF-301 has also demonstrated impressive anti-biofilm activity in vitro .…”

Section: Phage Lysinsmentioning

confidence: 99%

Efficacy of Phage- and Bacteriocin-Based Therapies in Combatting Nosocomial MRSA Infections

Walsh

Johnson

Hill

et al. 2021

Front. Mol. Biosci.

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Staphylococcus aureus is a pathogen commonly found in nosocomial environments where infections can easily spread - especially given the reduced immune response of patients and large overlap between personnel in charge of their care. Although antibiotics are available to treat nosocomial infections, the increased occurrence of antibiotic resistance has rendered many treatments ineffective. Such is the case for methicillin resistant S. aureus (MRSA), which has continued to be a threat to public health since its emergence. For this reason, alternative treatment technologies utilizing antimicrobials such as bacteriocins, bacteriophages (phages) and phage endolysins are being developed. These antimicrobials provide an advantage over antibiotics in that many have narrow inhibition spectra, enabling treatments to be selected based on the target (pathogenic) bacterium while allowing for survival of commensal bacteria and thus avoiding collateral damage to the microbiome. Bacterial resistance to these treatments occurs less frequently than with antibiotics, particularly in circumstances where combinatory antimicrobial therapies are used. Phage therapy has been well established in Eastern Europe as an effective treatment against bacterial infections. While there are no Randomized Clinical Trials (RCTs) to our knowledge examining phage treatment of S. aureus infections that have completed all trial phases, numerous clinical trials are underway, and several commercial phage preparations are currently available to treat S. aureus infections. Bacteriocins have primarily been used in the food industry for bio-preservation applications. However, the idea of repurposing bacteriocins for human health is an attractive one considering their efficacy against many bacterial pathogens. There are concerns about the ability of bacteriocins to survive the gastrointestinal tract given their proteinaceous nature, however, this obstacle may be overcome by altering the administration route of the therapy through encapsulation, or by bioengineering protease-resistant variants. Obstacles such as enzymatic digestion are less of an issue for topical/local administration, for example, application to the surface of the skin. Bacteriocins have also shown impressive synergistic effects when used in conjunction with other antimicrobials, including antibiotics, which may allow antibiotic-based therapies to be used more sparingly with less resistance development. This review provides an updated account of known bacteriocins, phages and phage endolysins which have demonstrated an impressive ability to kill S. aureus strains. In particular, examples of antimicrobials with the ability to target MRSA strains and their subsequent use in a clinical setting are outlined.

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Development of a Novel Chimeric Endolysin, Lys109 With Enhanced Lytic Activity Against Staphylococcus aureus

Cited by 34 publications

References 58 publications

The Holin-Endolysin Lysis System of the OP2-Like Phage X2 Infecting Xanthomonas oryzae pv. oryzae

The Holin-Endolysin Lysis System of the OP2-Like Phage X2 Infecting Xanthomonas oryzae pv. oryzae

Treating Bacterial Infections with Bacteriophage-Based Enzybiotics: In Vitro, In Vivo and Clinical Application

Efficacy of Phage- and Bacteriocin-Based Therapies in Combatting Nosocomial MRSA Infections

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