Specific Inhibition of VanZ-Mediated Resistance to Lipoglycopeptide Antibiotics

• Published in: International journal of molecular sciences 2021-12, Vol.23 (1), p.97
• Main Authors: Sur, Vishma Pratap, Mazumdar, Aninda, Vimberg, Vladimir, Stefani, Tommaso, Androvic, Ladislav, Kracikova, Lucie, Laga, Richard, Kamenik, Zdenek, Komrskova, Katerina
• Format: Article
• Language: English
• Subjects: Amino acids; Anti-Bacterial Agents - pharmacology; Antibiotic resistance; Antibiotics; Bacteria; Bacterial Proteins - metabolism; benzimidazole; Benzimidazoles; Binding sites; Biocompatibility; Cytotoxicity; docking; Drug resistance; Drug Resistance, Bacterial - drug effects; Enterococcus faecium; Genes; Genomes; Glycopeptides; Gram-positive bacteria; Gram-Positive Bacteria - drug effects; Gram-Positive Bacterial Infections - drug therapy; Humans; Hydrogen bonds; Infections; Ligands; lipoglycopeptide antibiotic; Lipoglycopeptides - pharmacology; Methicillin; Microbial Sensitivity Tests - methods; Molecular docking; Molecular Docking Simulation - methods; Prophylaxis; Protein structure; Proteins; Simulation; Streptococcus infections; Teicoplanin; Teicoplanin - pharmacology; Vancomycin; Vancomycin - pharmacology
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms23010097

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 , and . The expression of ( ), encoded either in the ( ) glycopeptide antibiotic resistance gene cluster or in the genomes of , as well as and , 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 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.