Research

Enzybiotics are a novel class of antibacterials, based on the peptidoglycan lysins, which kill rapidly and specifically the bacteria, preventing the appearance of crossed resistances with other pathogens and the microbiota degradation.

The common narrow lytic spectra of enzybiotics a novel and promising class of antibacterials relies, primarily, on their targeting of specific cell-wall receptors through specialized modules: the cell wall-binding domains. Using as model system the cell wall binding domain of the Cpl-7 endolysin (made of three identical CW_7 repeats), we have established the molecular basis for the cell wall recognition by the CW_7 motif, which is widely represented in sequences of cell wall hydrolases. To this aim, the crystal and solution 25 structures of the Cpl-7 cell wall-binding domain (C-Cpl-7) were solved, N-acetyl-Dglucosaminyl-(β1,4)-N-acetylmuramyl-L-alanyl-D-isoglutamine (GMDP) was identified as part of the peptidoglycan target recognized by the CW_7 motifs, and a plausible model of the C-Cpl-7 in complex with GMDP was generated. The potential use of CW_7-containing lysins as novel anti-infectives was also highlighted. In addition to sequence, the optimal number of CW_7 repeats in a given enzyme might depend on the accompanying catalytic domain/s, and/or the bacterial taxonomy. As a result, the Cpl-7 endolysin displays and extended-range of substrates whereas the Csl2 chimera, with the same catalytic module and a cell wall-binding domain made of two CW_7 repeats, shows a narrow lytic spectrum. Led by Dr. Margarita Menendez from IQFR, the research was a colaboration with the groups of Drs. Marta Bruix and Juan A. Hermoso (IQFR-CSIC), Pedro Garcia (CIB-CSIC) and Ruben M Buey (USal).

N Bustamante, M Iglesias-Bexiga, N Bernardo-García, N Silva-Martín, G. García, MA Campanero-Rhodes, E García, I Usón, RM Buey, P García, JA Hermoso, M Bruix, M Menéndez (2017). Deciphering how Cpl-7 cell wall-binding repeats recognize the bacterial peptidoglycan. Sci. Rep. 7(1):16494. doi: 10.1038/s41598-017-16392-4.

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