Specific Inhibition of VanZ-Mediated Resistance to Lipoglycopeptide Antibiotics

Abstract

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.

Functional Analysis of Hypothetical Proteins of Vibrio parahaemolyticus Reveals the Presence of Virulence Factors and Growth-Related Enzymes With Therapeutic Potential

“…We further identified the antibiotic resistance protein VanZ (MSR16_hyp_778 and MSR17_hyp_703), which reduces the binding of lipoglycopeptide antibiotics to cell wall components, resulting in resistance to teicoplanin and vancomycin antibiotics. 110 , 111 …”

“…108,109 We further identified the antibiotic resistance protein VanZ (MSR16_hyp_778 and MSR17_hyp_703), which reduces the binding of lipoglycopeptide antibiotics to cell wall components, resulting in resistance to teicoplanin and vancomycin antibiotics. 110,111 Toxin proteins and toxin transporters. The thermostable direct hemolysin (TDH) and the TDH related hemolysin (TRH) are both regarded to be key virulence factors in pathogenic strains of the bacteria V. parahaemolyticus.…”

Boar Sperm Cryopreservation Improvement Using Semen Extender Modification by Dextran and Pentaisomaltose

“…Additional binding interactions were used for molecular simulation studies. MD simulation was conducted for 50 ns according to a previous study [ 27 , 32 ], where the simulation process was conducted using the GROMACS 2020 package, utilizing a charmm36 all-atom force field using empirical, semi-empirical, and quantum mechanical energy functions for the molecular systems. The topology and parameter files for the input ligand files were generated on the CGenff server ( , accessed on 10 December 2021).…”

“…The topology and parameter files for the input ligand files were generated on the CGenff server ( , accessed on 10 December 2021). The trajectory files were analyzed using GROMCAS tools—gmx rmsd, gmx gyrate, gmx sasa, gmx hbond, and gmx energy—for extracting the plot of the root mean square deviation (RMSD), root mean square fluctuations (RMSFs), radius of gyration (Rg), solvent accessible surface area (SASA), and hydrogen bond (H-bonds) [ 27 , 32 ].…”

Redefining Antibacterial Strategies with computational Screening of Benzimidazole Ligands Against VanZ Protein for Alternatives of Antibiotic.

“…The emergence of antibiotic-resistant pathogenic bacteria has decreased the effectivity of novel antimicrobials and increased the need to develop a treatment against these pathogens as well as the existing antibiotics [1][2][3]. Various studies reporting antimicrobial resistance has been published by numerous scientists across the globe [1,2,[4][5][6][7]. The evolution of vancomycin-resistant S. aureus (VRSA) and methicillin-resistant S. aureus (MRSA) has been reported by Bouche et al, 2010 [8]and Loomba et al, 2010[9].…”