Teicoplanin is a natural lipoglycopeptide antibiotic with a similar activity spectrum as vancomycin; however, it has with the added benefit to the patient of low cytotoxicity. Both teicoplanin and vancomycin antibiotics are actively used in medical practice in the prophylaxis and treatment of severe life-threatening infections caused by gram-positive bacteria, including methicillin-resistant Staphylococcus aureus, Enterococcus faecium and Clostridium difficile. The expression of vancomycin Z (vanZ), encoded either in the vancomycin A (vanA) glycopeptide antibiotic resistance gene cluster or in the genomes of E. faecium, as well as Streptococcus pneumoniae and C. difficile, was shown to specifically compromise the antibiotic efficiency through the inhibition of teicoplanin binding to the bacterial surface. However, the exact mechanisms of this action and protein structure remain unknown. In this study, the three-dimensional structure of VanZ from E. faecium EnGen0191 was predicted by using the I-TASSER web server. Based on the VanZ structure, a benzimidazole based ligand was predicted to bind to the VanZ by molecular docking. Importantly, this new ligand, named G3K, was further confirmed to specifically inhibit VanZ-mediated resistance to teicoplanin in vivo.

Department of Polymer and Colloid Immunotherapeutics Institute of Macromolecular Chemistry of the Czech Academy of Sciences Heyrovskeho namesti 2 162 06 Prague Czech Republic

Department of Polymers Faculty of Chemical Technology University of Chemistry and Technology Technicka 5 166 28 Prague Czech Republic

Department of Zoology Faculty of Science Charles University Vinicna 7 128 44 Prague Czech Republic

Laboratory for Biology of Secondary Metabolism Institute of Microbiology of the Czech Academy of Sciences Videnska 1083 142 20 Prague Czech Republic

Laboratory of Reproductive Biology Institute of Biotechnology of the Czech Academy of Sciences BIOCEV Prumyslova 595 252 50 Vestec Czech Republic

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