Abstract
The increasing emergence of multi-drug resistant streptococci poses a serious threat to public health worldwide. Bacteriophage lysins are promising alternatives to antibiotics; however, their narrow lytic spectrum restricted to closely related species is a central shortcoming to their translational development. Here, we describe an efficient method for rapid screening of engineered chimeric lysins and report a unique “chimeolysin”, ClyR, with robust activity and an extended-spectrum streptococcal host range against most streptococcal species, including S. pyogenes, S. agalactiae, S. dysgalactiae, S. equi, S. mutans, S. pneumoniae, S. suis and S. uberis, as well as representative enterococcal and staphylococcal species (including MRSA and VISA). ClyR is the first lysin that demonstrates activity against the dominant dental caries-causing pathogen as well as the first lysin that kills all four of the bovine mastitis-causing pathogens. This study demonstrates the success of the screening method resulting in a powerful lysin with potential for treating most streptococcal associated infections.
Highlights
Regulatory approval for each new protein therapeutic[11,12]
We demonstrate that ClyR has broad-spectrum lytic activity against most streptococcal species and is protective in an in vivo bacteremia model
Because ClyR displays high lytic activity against S. dysgalactiae, we evaluated the bacteriolytic properties of ClyR against this organism and other mastitis-causing streptococci in milk
Summary
Regulatory approval for each new protein therapeutic[11,12]. For example, the host range of PAL and Cpl-1 is almost exclusive to S. pneumoniae (Supplementary Table S1). Identification of lysins with high activity against an expanded host range, thereby increasing potential therapeutic applications, is needed to overcome financial hurdles associated with pharmaceutical development of this class of enzyme. Our approach combines expression of a chimeolysin library, constructed from donor CD and CBD domains, in an E. coli expression system combined with the aid of a novel enzyme, ClyN, which causes temporally controlled lysis of E. coli cells. Release of active chimeolysins by ClyN allows for screening of lytic activity against target species directly on culture plates (Supplementary Fig. S1). Using this method, we discovered and subsequently characterized a unique chimeolysin, ClyR. We demonstrate that ClyR has broad-spectrum lytic activity against most streptococcal species and is protective in an in vivo bacteremia model
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