Csl2, a novel chimeric bacteriophage lysin to fight infections caused by Streptococcus suis, an emerging zoonotic pathogen

Abstract

Streptococcus suis is a Gram-positive bacterium that infects humans and various animals, causing human mortality rates ranging from 5 to 20%, as well as important losses for the swine industry. In addition, there is no effective vaccine for S. suis and isolates with increasing antibiotic multiresistance are emerging worldwide. Facing this situation, wild type or engineered bacteriophage lysins constitute a promising alternative to conventional antibiotics. In this study, we have constructed a new chimeric lysin, Csl2, by fusing the catalytic domain of Cpl-7 lysozyme to the CW_7 repeats of LySMP lysin from an S. suis phage. Csl2 efficiently kills different S. suis strains and shows noticeable activity against a few streptococci of the mitis group. Specifically, 15 µg/ml Csl2 killed 4.3 logs of S. suis serotype 2 S735 strain in 60 min, in a buffer containing 150 mM NaCl and 10 mM CaCl2, at pH 6.0. We have set up a protocol to form a good biofilm with the non-encapsulated S. suis mutant strain BD101, and the use of 30 µg/ml Csl2 was enough for dispersing such biofilms and reducing 1–2 logs the number of planktonic bacteria. In vitro results have been validated in an adult zebrafish model of infection.

Engineering of Phage-Derived Lytic Enzymes: Improving Their Potential as Antimicrobials

“…The generated chimeolysin, Csl2, displayed superior bactericidal and antibiofilm activity when compared to LysSMP. At the highest dose, Csl2 fully protected adult zebrafish from lethal S. suis infection [ 72 ].…”

Phage Lysins for Fighting Bacterial Respiratory Infections: A New Generation of Antimicrobials

“…The enzymatic activity of lysins was the basis for their exploration as antibacterial agents and they were also named “enzybiotics” ( 27 ). Lysins possess several advantages over antibiotics: (a) they rapidly kill bacteria, practically upon contact; (b) they can be specific to the target pathogen, particularly against Gram-positive (G+) bacteria ( 28 – 31 ), which allows to preserve the normal microbiota ( 32 ); (c) development of resistance seems very unlikely ( 33 , 34 ), probably because these enzymes directly target an essential and well-conserved structural component such as the PG, which cannot be easily modified without compromising fitness ( 35 ); (d) with few exceptions ( 36 , 37 ), lysins are active independently of the bacterial physiological state ( 38 , 39 ); (e) they are effective against MDR bacteria ( 20 , 34 , 40 – 42 ); (f) they can act synergistically with other lysins or antibiotics and thus theoretically reduce the development of resistance while increasing therapeutic efficiency; and (g) lysins are also effective killing colonizing pathogens growing on mucosal surfaces and/or in biofilms (Tables 1 , 2 ).…”

Phages for Biofilm Removal

“…An example is the chimeric lysin Csl2, obtained by fusion of the catalytic domain of Cp1-7 lysozyme to the CW-7 repeats of the LySMP lysine from a Staphylococcus suis phage. It was designed to remove S. suis biofilms with positive results in vitro, and validated in vivo with a zebrafish infection model [79].…”

“…One of the main interesting features of lysins as therapeutic agents is that their activity is independent of the bacterial physiological state [79]. It was shown that the use of Art-175 lysine against multi-drug-resistant P. aeruginosa biofilms caused osmotic lysis independent of bacterial metabolism.…”