Lysins breaking down the walls of Gram-negative bacteria, no longer a no-go

Gutiérrez, Diana; Briers, Yves

doi:10.1016/j.copbio.2020.08.014

Cited by 51 publications

(49 citation statements)

References 48 publications

(60 reference statements)

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“…Endolysins have been successfully used as alternative antibacterials against diverse pathogenic bacteria, displaying low probability of resistance development (Nelson et al, 2012). However, their antibacterial activity is generally limited toward Gram-positive bacteria, as Gram-negative bacteria possess an outer membrane that hinders access of endolysins to the peptidoglycan layer (Fernández-Ruiz et al, 2018;Gutiérrez and Briers, 2021). Over the last decade, research has been focused on developing approaches to enable endolysins to overcome the outer membrane barrier of Gram-negative bacteria.…”

Section: Introductionmentioning

confidence: 99%

Developing Innolysins Against Campylobacter jejuni Using a Novel Prophage Receptor-Binding Protein

et al. 2021

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Campylobacter contaminated poultry remains the major cause of foodborne gastroenteritis worldwide, calling for novel antibacterials. We previously developed the concept of Innolysin composed of an endolysin fused to a phage receptor binding protein (RBP) and provided the proof-of-concept that Innolysins exert bactericidal activity against Escherichia coli. Here, we have expanded the Innolysin concept to target Campylobacter jejuni. As no C. jejuni phage RBP had been identified so far, we first showed that the H-fiber originating from a CJIE1-like prophage of C. jejuni CAMSA2147 functions as a novel RBP. By fusing this H-fiber to phage T5 endolysin, we constructed Innolysins targeting C. jejuni (Innolysins Cj). Innolysin Cj1 exerts antibacterial activity against diverse C. jejuni strains after in vitro exposure for 45 min at 20°C, reaching up to 1.30 ± 0.21 log reduction in CAMSA2147 cell counts. Screening of a library of Innolysins Cj composed of distinct endolysins for growth inhibition, allowed us to select Innolysin Cj5 as an additional promising antibacterial candidate. Application of either Innolysin Cj1 or Innolysin Cj5 on chicken skin refrigerated to 5°C and contaminated with C. jejuni CAMSA2147 led to 1.63 ± 0.46 and 1.18 ± 0.10 log reduction of cells, respectively, confirming that Innolysins Cj can kill C. jejuni in situ. The receptor of Innolysins Cj remains to be identified, however, the RBP component (H-fiber) recognizes a novel receptor compared to lytic phages binding to capsular polysaccharide or flagella. Identification of other unexplored Campylobacter phage RBPs may further increase the repertoire of new Innolysins Cj targeting distinct receptors and working as antibacterials against Campylobacter.

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Section: Introductionmentioning

confidence: 99%

Developing Innolysins Against Campylobacter jejuni Using a Novel Prophage Receptor-Binding Protein

et al. 2021

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“…However, very few of them reach the advanced preclinical and clinical phases of development, among which are recombinant lysins against Staphylococcus aureus SAL200 (tonabacase; Jun et al, 2017 ) and CF -301 (exebacase; Fowler et al, 2020 ) for systemic administration and topical endolysins for the treatment of atopic dermatitis infected with S. aureus (Gladskin; Totté et al, 2017 ) and for prevention of nasal MRSA colonization (GangaGen, ClinicalTrials.gov Identifier: NCT01746654). Endolysin-based formulations against Gram-positive bacteria (especially S. aureus ) predominate in late preclinical or clinical experience despite the fact that recent studies have also shown effectiveness of endolysins against highly resistant Gram-negative bacteria-caused infections ( Gutiérrez and Briers, 2021 ).…”

Section: Introductionmentioning

confidence: 99%

Discovering the Potentials of Four Phage Endolysins to Combat Gram-Negative Infections

et al. 2021

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Endolysin-based therapeutics are promising antibacterial agents and can successfully supplement the existing antibacterial drugs array. It is specifically important in the case of Gram-negative pathogens, e.g., ESKAPE group bacteria, which includes Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species, and are highly inclined to gain multiple antibiotic resistance. Despite numerous works devoted to the screening of new lytic enzymes and investigations of their biochemical properties, there are significant breaches in some aspects of their operating characteristics, including safety issues of endolysin use. Here, we provide a comprehensive study of the antimicrobial efficacy aspects of four Gram-negative bacteria-targeting endolysins LysAm24, LysAp22, LysECD7, and LysSi3, their in vitro and in vivo activity, and their biological safety. These endolysins possess a wide spectrum of action, are active against planktonic bacteria and bacterial biofilms, and are effective in wound and burn skin infection animal models. In terms of safety, these enzymes do not contribute to the development of short-term resistance, are not cytotoxic, and do not significantly affect the normal intestinal microflora in vivo. Our results provide a confident base for the development of effective and safe candidate dosage forms for the treatment of local and systemic infections caused by Gram-negative bacterial species.

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“…Compared with phages, the application of lysins, which are derived from phages, has been widely studied in recent years (Wang et al, 2018;Raz et al, 2019); in particular, lysins of phages that overcome Gram-positive pathogens infection (Rios et al, 2016;Wang et al, 2018). However, lysins were not initially recommended against Gram-negative pathogens because their impermeable outer membrane blocked lysin contact with peptidoglycans, which is the target of lysins (Gutierrez and Briers, 2020). Phage PAJD-1 had a strong bactericidal effect against a broad spectrum of bacteria, suggesting that the lysin encoded by the phage had a strong bactericidal effect.…”

Section: Discussionmentioning

confidence: 99%

“…Phages are the most common organism found on earth and, as such, represent great diversity in their overall host range (Khalid et al, 2020). The bacteriolysis of phages is mainly dependent on endolysin (termed lysin), which is a kind of bacterial cell wall hydrolase synthesized by phages in the late stages of infection (Wang et al, 2018;Gutierrez and Briers, 2020). Compared to traditional antibiotics, bacteriophage agents have obvious advantages, such as being simple, cheap, highly effective in killing their target bacteria and especially available in inhibiting drug-resistant bacteria, as well as causing no serious side effects (Hesse and Adhya, 2019;Principi et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

Phage vB_PaeS-PAJD-1 Rescues Murine Mastitis Infected With Multidrug-Resistant Pseudomonas aeruginosa

Wang

Xue

Gao

et al. 2021

Front. Cell. Infect. Microbiol.

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Pseudomonas aeruginosa is a Gram-negative pathogen that causes a variety of infections in humans and animals. Due to the inappropriate use of antibiotics, multi-drug resistant (MDR) P. aeruginosa strains have emerged and are prevailing. In recent years, cow mastitis caused by MDR P. aeruginosa has attracted attention. In this study, a microbial community analysis revealed that P. aeruginosa could be a cause of pathogen-induced cow mastitis. Five MDR P. aeruginosa strains were isolated from milk diagnosed as mastitis positive. To seek an alternative antibacterial agent against MDR, P. aeruginosa, a lytic phage, designated vB_PaeS_PAJD-1 (PAJD-1), was isolated from dairy farm sewage. PAJD-1 was morphologically classified as Siphoviridae and was estimated to be about 57.9 kb. Phage PAJD-1 showed broad host ranges and a strong lytic ability. A one-step growth curve analysis showed a relatively short latency period (20 min) and a relatively high burst size (223 PFU per infected cell). Phage PAJD-1 remained stable over wide temperature and pH ranges. Intramammary-administered PAJD-1 reduced bacterial concentrations and repaired mammary glands in mice with mastitis induced by MDR P. aeruginosa. Furthermore, the cell wall hydrolase (termed endolysin) from phage PAJD-1 exhibited a strong bacteriolytic and a wide antibacterial spectrum against MDR P. aeruginosa. These findings present phage PAJD-1 as a candidate for phagotherapy against MDR P. aeruginosa infection.

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Lysins breaking down the walls of Gram-negative bacteria, no longer a no-go

Cited by 51 publications

References 48 publications

Developing Innolysins Against Campylobacter jejuni Using a Novel Prophage Receptor-Binding Protein

Developing Innolysins Against Campylobacter jejuni Using a Novel Prophage Receptor-Binding Protein

Discovering the Potentials of Four Phage Endolysins to Combat Gram-Negative Infections

Phage vB_PaeS-PAJD-1 Rescues Murine Mastitis Infected With Multidrug-Resistant Pseudomonas aeruginosa

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