Are Phage Lytic Proteins the Secret Weapon To Kill Staphylococcus aureus?

Abstract

Methicillin-resistant Staphylococcus aureus (MRSA) is one of the most threatening microorganisms for global human health. The current strategies to reduce the impact of S. aureus include a restrictive control of worldwide antibiotic use, prophylactic measures to hinder contamination, and the search for novel antimicrobials to treat human and animal infections caused by this bacterium. The last strategy is currently the focus of considerable research. In this regard, phage lytic proteins (endolysins and virion-associated peptidoglycan hydrolases [VAPGHs]) have been proposed as suitable candidates. Indeed, these proteins display narrow-spectrum antimicrobial activity and a virtual lack of bacterial-resistance development. Additionally, the therapeutic use of phage lytic proteins in S. aureus animal infection models is yielding promising results, showing good efficacy without apparent side effects. Nonetheless, human clinical trials are still in progress, and data are not available yet. This minireview also analyzes the main obstacles for introducing phage lytic proteins as human therapeutics against S. aureus infections. Besides the common technological problems derived from large-scale production of therapeutic proteins, a major setback is the lack of a proper legal framework regulating their use. In that sense, the relevant health authorities should urgently have a timely discussion about these new antimicrobials. On the other hand, the research community should provide data to dispel any doubts regarding their efficacy and safety. Overall, the appropriate scientific data and regulatory framework will encourage pharmaceutical companies to invest in these promising antimicrobials.

Keywords: Staphylococcus aureus; bacteriophage; bacteriophage therapy; endolysin.

FIG 1

(A) Bacteriophage lytic cycle. 1, Adsorption of phage to the bacterium; 2, injection of genetic material into the cytoplasm; 3, replication of phage genetic material; 4, synthesis of phage components; 5, assembly of new phage particles; 6, bacterial lysis and release of phage particles. (B) Role of phage lytic proteins in the phage life cycle. VAPGHs favor the injection of phage genetic material into the cytoplasm by the formation of a hole in the cell wall. Endolysins and holins are produced at the end of the life cycle. Holins form a pore in the bacterial membrane, allowing the endolysin to reach the peptidoglycan.

FIG 2

Structure and enzymatic activities of phage lytic proteins against S. aureus peptidoglycan. (A) The typical modular structure of phage lytic proteins (endolysins and VAPGHs) is represented by the catalytic domains and the cell wall binding domains (CBDs). (B) The structure of S. aureus peptidoglycan is shown, and the enzymatic activities of the proteins are indicated with an arrow and a number. 1, N-Acetylmuramoyl-l-alanine amidase; 2, interpeptide bridge endopeptidase; 3, l-alanoyl-d-glutamate endopeptidase; 4, N-acetyl-β-d-muramidase; 5, transglycosylase; 6, N-acetyl-β-d-glucosaminidase.

FIG 3

Schematic representation of the domain shuffling strategy to obtain chimeric proteins from two phage lytic proteins. C1, C2, and C3 represent catalytic domains, while CBD1 and CBD2 represent different cell wall binding domains.

FIG 4

Current applications of S. aureus phage lytic proteins in human and animal therapy (A) and improvement of food safety (B).