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Review
, 31 (1)

Recombinant Endolysins as Potential Therapeutics Against Antibiotic-Resistant Staphylococcus Aureus: Current Status of Research and Novel Delivery Strategies

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Review

Recombinant Endolysins as Potential Therapeutics Against Antibiotic-Resistant Staphylococcus Aureus: Current Status of Research and Novel Delivery Strategies

Hamed Haddad Kashani et al. Clin Microbiol Rev.

Abstract

Staphylococcus aureus is one of the most common pathogens of humans and animals, where it frequently colonizes skin and mucosal membranes. It is of major clinical importance as a nosocomial pathogen and causative agent of a wide array of diseases. Multidrug-resistant strains have become increasingly prevalent and represent a leading cause of morbidity and mortality. For this reason, novel strategies to combat multidrug-resistant pathogens are urgently needed. Bacteriophage-derived enzymes, so-called endolysins, and other peptidoglycan hydrolases with the ability to disrupt cell walls represent possible alternatives to conventional antibiotics. These lytic enzymes confer a high degree of host specificity and could potentially replace or be utilized in combination with antibiotics, with the aim to specifically treat infections caused by Gram-positive drug-resistant bacterial pathogens such as methicillin-resistant S. aureus. LysK is one of the best-characterized endolysins with activity against multiple staphylococcal species. Various approaches to further enhance the antibacterial efficacy and applicability of endolysins have been demonstrated. These approaches include the construction of recombinant endolysin derivatives and the development of novel delivery strategies for various applications, such as the production of endolysins in lactic acid bacteria and their conjugation to nanoparticles. These novel strategies are a major focus of this review.

Keywords: Staphylococcus aureus; antibiotic resistance; endolysin; infectious diseases; nanoparticles; probiotic bacteria.

Figures

FIG 1
FIG 1
The cell wall structure of Gram-positive bacteria contains a thick layer of peptidoglycan that resides beyond the cytoplasmic membrane.
FIG 2
FIG 2
The modular structure of the LysK endolysin, consisting of 2 enzymatically active domains (CHAP and amidase-2) and one bacterial SH3 (SH3b) cell wall-binding domain.
FIG 3
FIG 3
Schematic representation of S. aureus peptidoglycan and LysK cleavage sites. The peptidoglycan is made up of sugar strands consisting of two alternating units (N-acetylmuramic acid and N-acetylglucosamine) and peptide linkers connecting these strands. Five units of glycine (Gly) act as a cross-bridge between stem peptides.
FIG 4
FIG 4
Protein secretion pathway in the nisin-controlled gene expression system in L. lactis. After nisin is detected by the sensor histidine kinase protein located in the membrane (NisK), autophosphorylation of this protein occurs, followed by the transfer of its phosphatase group to the cytoplasmic response regulator NisR. NisR, which is now activated, then activates transcription via the PnisA promoter, followed by the production of a target protein, which in this case is a recombinant endolysin. Depending on the presence or absence of a specific signal peptide, the protein either is secreted into the external medium or accumulates in the cytoplasm.
FIG 5
FIG 5
Schematic structure of an antibiotic-nanoparticle conjugate reacting with receptors within the cytoplasmic membrane. Ag-NP, silver nanoparticle; ABX, any kind of natural, synthetic, or recombinant antibiotic.
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