Abstract
Endolysins, the cell wall lytic enzymes encoded by bacteriophages to release the phage progeny, are among the top alternatives to fight against multiresistant pathogenic bacteria; one of the current biggest challenges to global health. Their narrow range of susceptible bacteria relies, primarily, on targeting specific cell-wall receptors through specialized modules. The cell wall-binding domain of Cpl-7 endolysin, made of three CW_7 repeats, accounts for its extended-range of substrates. Using as model system the cell wall-binding domain of Cpl-7, here we describe the molecular basis for the bacterial cell wall recognition by the CW_7 motif, which is widely represented in sequences of cell wall hydrolases. We report the crystal and solution structure of the full-length domain, identify N-acetyl-D-glucosaminyl-(β1,4)-N-acetylmuramyl-L-alanyl-D-isoglutamine (GMDP) as the peptidoglycan (PG) target recognized by the CW_7 motifs, and characterize feasible GMDP-CW_7 contacts. Our data suggest that Cpl-7 cell wall-binding domain might simultaneously bind to three PG chains, and also highlight the potential use of CW_7-containing lysins as novel anti-infectives.
Highlights
Antibiotic-resistant bacteria are especially promiscuous and constitute an increasing source of healthcare and economic concerns
The catalytic units dictate the type of peptidoglycan (PG) bond to be cleaved, whereas the cell wall-binding domain(s) largely determines the lytic spectrum by specific recognition of cell wall elements distributed in genus, or species/strain-specific manner[5,10,12]
By means of saturation transfer difference NMR spectroscopy (STD-NMR) we have demonstrated that GMDP is recognized as a ligand by the CW_7 repeats, and the binding epitope of this fragment of the PG monomer has been identified
Summary
Antibiotic-resistant bacteria are especially promiscuous and constitute an increasing source of healthcare and economic concerns. The cell wall lytic enzymes encoded by bacteriophages (endolysins) or bacteria (autolysins), have attracted much attention because of their ability to break-down the cell wall of target bacteria when added exogenously (lysis-from-without)[1,2]. This novel class of antibacterials has important advantages over classical antibiotics, e.g., a novel mode of action; a narrow spectrum of susceptible bacteria; rapid killing of both stationary- and exponentially-growing bacteria; activity on mucous membranes and bacterial biofilms; low probability of developing resistances; and reduced impact on normal microbiota[3,4,5]. Our results shed light on the fine interactions established between key amino acid residues of CW_7 repeats and the building blocks of the PG, providing a rational for the use of this cell wall-binding motif in lysin design and applications
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