Bacteriophage-derived endolysins to target gram-negative bacteria

Lai, Wing Ching Bianca; Chen, Xi; Ho, Marco Kai Yuen; Xia, Jiang; Leung, Sharon Shui Yee

doi:10.1016/j.ijpharm.2020.119833

Cited by 61 publications

(62 citation statements)

References 91 publications

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“…1A) As a whole, however, the differential relative amount of single and multiple PF hits sequences between G and G+ phage lysins ( Fig. 1A and E) can be taken into account, in accordance with the usual proposal that G-lysins are typically monomodular, while G+ ones are multimodular (46). This is further supported by the evident difference in protein length distributions ( Fig.…”

Section: Resultssupporting

confidence: 84%

Sequence-function Relationships in Phage-encoded Bacterial Cell Wall Lytic Enzymes and their Implications for Phage-derived Products Design

Vázquez

Garcı́a

2021

Preprint

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Phage (endo)lysins are thought to be a viable alternative to usual antibiotic chemotherapy to fight resistant bacterial infections. However, a landscape view of lysins' structure and properties regarding their function, with an applied focus, is somewhat lacking. Current literature suggests that specific features typical of lysins from phages infecting Gram-negative bacteria (G−) (higher net charge, amphipathic helices) are responsible for an improved interaction with G− envelope. Such antimicrobial peptide (AMP)-like elements are also of interest for antimicrobial molecules design. Thus, this study aims to provide an updated view on the primary structural landscape of phage lysins to clarify the evolutionary importance of several sequence-predicted properties, particularly for the interaction with the G− surface. A database of 2,182 lysin sequences was compiled, containing relevant information such as domain architectures, data on the phages’ host bacteria and sequence-predicted physicochemical properties. Based on such classifiers, an investigation on the differential appearance of certain features was conducted. Such analyses revealed different lysin architectural variants that are preferably found in phages infecting certain bacterial hosts. Particularly, some physicochemical properties (higher net charge, hydrophobicity, hydrophobic moment and aliphatic index) were associated to G− phage lysins, appearing specifically at their C-terminal end. Evidences on the remarkable genetic specialization of lysins regarding the features of the bacterial hosts have been provided, specifically supporting the nowadays common hypothesis that lysins from G− usually contain AMP-like regions.

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Section: Resultssupporting

confidence: 84%

Sequence-function Relationships in Phage-encoded Bacterial Cell Wall Lytic Enzymes and their Implications for Phage-derived Products Design

Vázquez

Garcı́a

2021

Preprint

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“…As a whole, however, the differential relative amount of single and multiple PF hits sequences between G and G+ phage lysins (Fig. 2A and B) can be taken into account, on May 2, 2021 by guest http://jvi.asm.org/ Downloaded from in accordance with the usual proposal that G-lysins are typically monomodular, while G+ ones are multimodular (46). Fig.…”

Section: Resultssupporting

confidence: 77%

Sequence-Function Relationships in Phage-Encoded Bacterial Cell Wall Lytic Enzymes and Their Implications for Phage-Derived Product Design

Vázquez

Garcı́a

2021

J Virol

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Phage (endo)lysins are thought to be a viable alternative to usual antibiotic chemotherapy to fight resistant bacterial infections. However, a landscape view of lysins’ structure and properties regarding their function, with an applied focus, is somewhat lacking. Current literature suggests that specific features typical of lysins from phages infecting Gram-negative bacteria (G−) (higher net charge, amphipathic helices) are responsible for improved interaction with the G− envelope. Such antimicrobial peptide (AMP)-like elements are also of interest for antimicrobial molecules design. Thus, this study aims to provide an updated view on the primary structural landscape of phage lysins to clarify the evolutionary importance of several sequence-predicted properties, particularly for the interaction with the G− surface. A database of 2,182 lysin sequences was compiled, containing relevant information such as domain architectures, data on the phages’ host bacteria, and sequence-predicted physicochemical properties. Based on such classifiers, an investigation of the differential appearance of certain features was conducted. Such analyses revealed different lysin architectural variants that are preferably found in phages infecting certain bacterial hosts. Particularly, some physicochemical properties (higher net charge, hydrophobicity, hydrophobic moment, and aliphatic index) were associated with G− phage lysins, appearing specifically at their C-terminal end. Evidence on the remarkable genetic specialization of lysins regarding the features of the bacterial hosts has been provided, specifically supporting the nowadays common hypothesis that lysins from G− usually contain AMP-like regions. IMPORTANCE Phage-encoded lytic enzymes, also called lysins, are one of the most promising alternatives to common antibiotics. The potential of lysins as novel antimicrobials to tackle antibiotic-resistant bacteria not only arises from features such as a lower chance to provoke resistance, but also from their versatility as synthetic biology parts. Functional modules derived from lysins are currently being used for the design of novel antimicrobials with desired properties. This study provides a view of the lysins diversity landscape by examining a set of phage lysin genes. This way, we have uncovered the fundamental differences between the lysins from phages that infect bacteria with different superficial architectures, and, thus, also the reach of their specialization regarding cell wall structures. These results provide clarity and evidence to sustain some of the common hypotheses in current literature, as well as make available an updated and characterized database of lysins sequences for further developments.

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“…Lysins frequently show modular architecture, combining catalytic domain(s) with or without a cell wall-binding domain that corresponds to host specificity [8]. However, Gram-negative bacteria have an outer membrane covering the peptidoglycan layer, which make them more resistant to the external treatments of lysins than Gram-positive bacteria [9].…”

Section: Introductionmentioning

confidence: 99%

LysSAP26, a New Recombinant Phage Endolysin with a Broad Spectrum Antibacterial Activity

Kim

Jin

Choi

et al. 2020

Viruses

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Multidrug-resistant (MDR) bacteria are a major threat to public health. Bacteriophage endolysins (lysins) are a promising alternative treatment to traditional antibiotics. However, the lysins currently under development are still underestimated. Herein, we cloned the lysin from the SAP-26 bacteriophage genome. The recombinant LysSAP26 protein inhibited the growth of carbapenem-resistant Acinetobacter baumannii, Escherichia coli, Klebsiella pneumoniae, and Pseudomonas aeruginosa, oxacillin-resistant Staphylococcus aureus, and vancomycin-resistant Enterococcus faecium with minimum inhibitory concentrations of 5~80 µg/mL. In animal experiments, mice infected with A. baumannii were protected by LysSAP26, with a 40% survival rate. Transmission electron microscopy analysis confirmed that LysSAP26 treatment resulted in the destruction of bacterial cell walls. LysSAP26 is a new endolysin that can be applied to treat MDR A. baumannii, E. faecium, S. aureus, K. pneumoniae, P. aeruginosa, and E. coli infections, targeting both Gram-positive and Gram-negative bacteria.

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Bacteriophage-derived endolysins to target gram-negative bacteria

Cited by 61 publications

References 91 publications

Sequence-function Relationships in Phage-encoded Bacterial Cell Wall Lytic Enzymes and their Implications for Phage-derived Products Design

Sequence-function Relationships in Phage-encoded Bacterial Cell Wall Lytic Enzymes and their Implications for Phage-derived Products Design

Sequence-Function Relationships in Phage-Encoded Bacterial Cell Wall Lytic Enzymes and Their Implications for Phage-Derived Product Design

LysSAP26, a New Recombinant Phage Endolysin with a Broad Spectrum Antibacterial Activity

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