Specific Inhibition of VanZ-Mediated Resistance to Lipoglycopeptide Antibiotics.

Vishma Pratap Sur,Vladimir Vimberg,Aninda Mazumdar,Zdenek Kamenik,Katerina Komrskova,Tommaso Stefani,Ladislav Androvic,Lucie Kracikova,Richard Laga

doi:10.3390/ijms23010097

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.

Highlights

Antibiotic resistance in bacteria represents a serious global threat requiring the search for new compounds to treat bacterial infectious diseases
Such bacteria outgrowth may result in enterococcal infections via direct bacterial translocation from the gut to the bloodstream, or via fecal contamination leading to the urinary tract, surgical-site infections, or colonization of the skin [10]
We used the I-TASSER web server to predict the 3D structure of VanZ

Summary

Introduction

Antibiotic resistance in bacteria represents a serious global threat requiring the search for new compounds to treat bacterial infectious diseases. The normal gut microbiota of patients are affected by the administration of broad-spectrum antibiotics, facilitating the outgrowth of antibiotic-resistant E. faecium Such bacteria outgrowth may result in enterococcal infections via direct bacterial translocation from the gut to the bloodstream, or via fecal contamination leading to the urinary tract, surgical-site infections, or colonization of the skin [10]. The natural glycopeptide antibiotic, vancomycin (VAN) and the natural lipoglycopeptide antibiotic, teicoplanin (TEI) [11], have been used as ‘last resort’ antibiotics to treat E. faecium infections. These antibiotics bind to the D-alanyl-D-alanine (D-Ala-DAla) terminus of the bacterial peptidoglycan precursor [12], resulting in the inhibition of the cell wall synthesis and subsequent cell lysis. Due to TEI’s efficiency and much lower cytotoxicity in comparison to VAN, TEI has been preferentially used in patients with medical complications, including pediatric and immune-compromised patients

Methods

Results

Conclusion