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.

Laboratory for Biology of Secondary Metabolism Institute of Microbiology of the Czech Academy of Sciences Prague Czechia

Laboratory of Cell Signaling Institute of Microbiology of the Czech Academy of Sciences Prague Czechia

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Arthur M., Depardieu F., Molinas C., Reynolds P., Courvalin P. (1995). The PubMed DOI

Arthur M., Depardieu F., Reynolds P., Courvalin P. (1999). Moderate-level resistance to glycopeptide LY333328 mediated by genes of the PubMed DOI PMC

Arthur M., Depardieu F., Snaith H. A., Reynolds P. E., Courvalin P. (1994). Contribution of vanY D, D-carboxypeptidase to glycopeptide resistance in PubMed DOI PMC

Beauregard D., Williams D. H., Gwynn M. N., Knowles D. J. (1995). Dimerization and membrane anchors in extracellular targeting of vancomycin group antibiotics. PubMed DOI PMC

Bugg T. D. H., Wright G. D., Dutkamalen S., Arthur M., Courvalin P., Walsh C. T. (1991). Molecular-basis for vancomycin resistance in PubMed DOI

Chang S., Sievert D. M., Hageman J. C., Boulton M. L., Tenover F. C., Downes F. P., et al. (2003). Infection with vancomycin-resistant PubMed

Csávás M., Miskovics A., Szcs Z., Röth E., Nagy Z. L., Bereczki I., et al. (2015). Synthesis and antibacterial evaluation of some teicoplanin pseudoaglycon derivatives containing alkyl-and arylthiosubstituted maleimides. PubMed DOI

Foucault M. L., Courvalin P., Grillot-Courvalin C. (2009). Fitness cost of VanA-type vancomycin resistance in methicillin-resistant PubMed DOI PMC

Hava D. L., Camilli A. (2002). Large-scale identification of serotype 4 PubMed DOI PMC

Kerns R., Dong S. D., Fukuzawa S., Carbeck J., Kohler J., Silver L., et al. (2000). The role of hydrophobic substituents in the biological activity of glycopeptide antibiotics. DOI

Kim S. J., Singh M., Sharif S., Schaefer J. (2017). Desleucyl-oritavancin with a damaged d -Ala- d -Ala binding site inhibits the transpeptidation step of cell-wall biosynthesis in whole cells of PubMed DOI PMC

Kim S. J., Tanaka K. S. E., Dietrich E., Rafai Far A., Schaefer J. (2013). Locations of the hydrophobic side chains of lipoglycopeptides bound to the peptidoglycan of PubMed DOI PMC

Lai L., Dai J., Tang H., Zhang S., Wu C., Qiu W., et al. (2017). Streptococcus suis serotype 9 strain GZ0565 contains a type VII secretion system putative substrate EsxA that contributes to bacterial virulence and a PubMed DOI

Lessard I. A. D., Walsh C. T. (1999). VanX, a bacterial D-alanyl-D-alanine dipeptidase: resistance, immunity, or survival function? PubMed DOI PMC

Li Y., Thompson C. M., Lipsitch M. (2014). A modified PubMed DOI PMC

Ng W. L., Kazmierczak K. M., Robertson G. T., Gilmour R., Winkler M. E. (2003). Transcriptional regulation and signature patterns revealed by microarray analyses of PubMed DOI PMC

Perichon B., Courvalin P. (2009). VanA-type vancomycin-resistant PubMed DOI PMC

Pintér G., Batta G., Kéki S., Mándi A., Komáromi I., Takács-Novák K., et al. (2009). Diazo transfer-click reaction route to new, lipophilic teicoplanin and ristocetin aglycon derivatives with high antibacterial and anti-influenza virus activity: an aggregation and receptor binding study. PubMed DOI

Saadat S., Solhjoo K., Norooz-Nejad M. J., Kazemi A. (2014). PubMed DOI PMC

Sung C. K., Li H., Claverys J. P., Morrison D. A. (2001). An PubMed DOI PMC

Szucs Z., Csávás M., Röth E., Borbás A., Batta G., Perret F., et al. (2017). Synthesis and biological evaluation of lipophilic teicoplanin pseudoaglycon derivatives containing a substituted triazole function. PubMed DOI

Uttley A. H. C., George R. C., Naidoo J., Woodford N., Johnson A. P., Collins C. H., et al. (1989). High-level vancomycin-resistant enterococci causing hospital infections. PubMed DOI PMC

Vimberg V., Gazak R., Szücs Z., Borbás A., Herczegh P., Cavanagh J. P., et al. (2019). Fluorescence assay to predict activity of the glycopeptide antibiotics. PubMed DOI

Woods E. C., Wetzel D., Mukerjee M., McBride S. M. (2018). Examination of the Clostridioides (Clostridium) difficile VanZ ortholog, CD1240. PubMed DOI PMC

Zeng D., Debabov D., Hartsell T. L., Cano R. J., Adams S., Schuyler J. A., et al. (2016). Approved glycopeptide antibacterial drugs: mechanism of action and resistance. PubMed DOI PMC

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