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.
Highlights
Antibiotics have been used as the common practice to prevent and treat infectious diseases in human, veterinary and agricultural fields during the last decades
Lysins hydrolyze the bacterial cell wall by breaking specific bonds of the peptidoglycan and, as a consequence, kill the bacteria rapidly upon contact, much faster than conventional antibiotics. They have other important advantages that can be summarized as follows: (a) lysins are, in general, very specific to the pathogen, which preserves the normal microbiome; (b) their bactericidal activity is independent of the bacterial physiological state; (c) lysins can act synergistically with conventional antibiotics and reduce the development of resistance to these drugs when administered concomitantly; (d) to date, no resistance mechanisms have been detected, probably because these enzymes target an essential and well conserved structural component like the peptidoglycan; (e) no signs of toxicity have been noticed after lysin treatment of systemic infections in mice models; (f) the immune response induced by lysins apparently neither neutralizes their activity nor prevents their use to treat systemic infections[17]
The other two characterized lysins comprising CW_7 repeats are λSa2lys from a Streptococcus agalactiae prophage[32] and LySMP from the S. suis SMP phage[9], both sharing the same type of architecture [Amidase_5-(CW_7)2− glucosaminidase]
Summary
Antibiotics have been used as the common practice to prevent and treat infectious diseases in human, veterinary and agricultural fields during the last decades. Macrolides, and tetracyclines reported worldwide for many S. suis isolates[15]; and (3) the lack of an effective vaccine for S. suis, which favours its rising presence in humans and hinders the treatment[16] All these facts make the case for searching alternative therapeutic agents against this bacterial pathogen. Lysins hydrolyze the bacterial cell wall by breaking specific bonds of the peptidoglycan and, as a consequence, kill the bacteria rapidly upon contact, much faster than conventional antibiotics They have other important advantages that can be summarized as follows: (a) lysins are, in general, very specific to the pathogen, which preserves the normal microbiome; (b) their bactericidal activity is independent of the bacterial physiological state; (c) lysins can act synergistically with conventional antibiotics and reduce the development of resistance to these drugs when administered concomitantly; (d) to date, no resistance mechanisms (or resistant phenotypes) have been detected, probably because these enzymes target an essential and well conserved structural component like the peptidoglycan; (e) no signs of toxicity have been noticed after lysin treatment of systemic infections in mice models; (f) the immune response induced by lysins apparently neither neutralizes their activity nor prevents their use to treat systemic infections[17]. These CW_7 repeats are essential for activity[25] and have been proposed to target a common structure of the peptidoglycan network[26]
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