VanZ Reduces the Binding of Lipoglycopeptide Antibiotics to Staphylococcus aureus and Streptococcus pneumoniae Cells.

Vladimir Vimberg,Gabriela Balíková Novotná,Leona Zieglerová,Pavel Branny,Karolína Buriánková

doi:10.3389/fmicb.2020.00566

Abstract

vanZ, a member of the VanA glycopeptide resistance gene cluster, confers resistance to lipoglycopeptide antibiotics independent of cell wall precursor modification by the vanHAX genes. Orthologs of vanZ are present in the genomes of many clinically relevant bacteria, including Enterococcus faecium and Streptococcus pneumoniae; however, vanZ genes are absent in Staphylococcus aureus. Here, we show that the expression of enterococcal vanZ paralogs in S. aureus increases the minimal inhibitory concentrations of lipoglycopeptide antibiotics teicoplanin, dalbavancin, oritavancin and new teicoplanin pseudoaglycone derivatives. The reduction in the binding of fluorescently labeled teicoplanin to the cells suggests the mechanism of VanZ-mediated resistance. In addition, using a genomic vanZ gene knockout mutant of S. pneumoniae, we have shown that the ability of VanZ proteins to compromise the activity of lipoglycopeptide antibiotics by reducing their binding is a more general feature of VanZ-superfamily proteins.

Highlights

Glycopeptide antibiotics are important for the treatment of multidrug-resistant infections caused by gram-positive bacteria
The ability of the E. faecium vanZTei and vanZg paralogs to confer resistance to glycopeptide antibiotics was tested in S. aureus, which naturally does not encode any proteins of the VanZ superfamily
We determined the susceptibility of S. aureus RN4220 expressing vanZTei and vanZg to the clinically used glycopeptide antibiotic vancomycin (VAN); the lipoglycopeptide antibiotics teicoplanin (TEI), oritavancin (ORI), and dalbavancin (DALB); and three experimental lipoglycopeptide antibiotics derived from teicoplanin pseudoaglycone: MA79 (Csávás et al, 2015), ERJ390 (Pintér et al, 2009) and SZZS-12 (Szucs et al, 2017; Figure 1)

Summary

Introduction

Glycopeptide antibiotics are important for the treatment of multidrug-resistant infections caused by gram-positive bacteria. The emergence and spread of enterococcal strains resistant to vancomycin and teicoplanin (VRE) is a serious public health concern (Uttley et al, 1989). In VRE-resistant strains, cell wall biosynthesis is reprogramed to produce peptidoglycan precursors containing either D-alanine-D-lactate (D-Ala-D-Lac) or D-alanine-D-serine instead of the dipeptide D-alanine-D-alanine (D-Ala-D-Ala). The three essential enzymes responsible for the precursor modification are encoded in vanHAX gene clusters. In the vanA-type gene cluster, two additional genes, vanY and vanZ, contribute to glycopeptide resistance. VanY, a D,D-carboxypeptidase, eliminates D-Ala-D-Ala from peptidoglycan precursors, minimizing the number of primary binding sites for glycopeptide antibiotics (Arthur et al, 1994). VanZ decreases the sensitivity of Enterococcus faecalis to teicoplanin and oritavancin, but not vancomycin, independent of peptidoglycan modification (Arthur et al, 1995, 1999)

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Conclusion