Characterisation of the selective binding of antibiotics vancomycin and teicoplanin by the VanS receptor regulating type A vancomycin resistance in the enterococci

• Published in: Biochimica et biophysica acta Vol. 1861; no. 8; pp. 1951 - 1959
• Main Authors: Hughes, C.S., Longo, E., Phillips-Jones, M.K., Hussain, R.
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.08.2017; Elsevier Pub. Co
• Subjects: Anti-Bacterial Agents - metabolism; Antibiotic resistance; Bacterial Proteins - chemistry; Bacterial Proteins - metabolism; Circular dichroism; Enterococci; Enterococcus; Enterococcus - drug effects; Enterococcus - metabolism; Fluorescence; glycopeptides; histidine; hospitals; ligands; pathogens; peptidoglycans; Phosphorylation; Protein Conformation; Protein Kinases - chemistry; Protein Kinases - metabolism; Teicoplanin; Teicoplanin - metabolism; Transcription Factors - chemistry; Transcription Factors - metabolism; tryptophan; tyrosine; United Kingdom; Vancomycin; Vancomycin - metabolism; Vancomycin Resistance; United Kingdom; CD; Enterococci; SRCD; VRE; HCD; Fluorescence; MSRCD; NMRSD; Vancomycin; MROs; Teicoplanin; Circular dichroism; LC-MS/MS; NAG; Antibiotic resistance; GPAs; NAM; UHPLC
• ISSN: 0304-4165; 0006-3002; 1872-8006; 1878-2434
• DOI: 10.1016/j.bbagen.2017.05.011

A-type resistance towards “last-line” glycopeptide antibiotic vancomycin in the leading hospital acquired infectious agent, the enterococci, is the most common in the UK. Resistance is regulated by the VanRASA two-component system, comprising the histidine sensor kinase VanSA and the partner response regulator VanRA. The nature of the activating ligand for VanSA has not been identified, therefore this work sought to identify and characterise ligand(s) for VanSA. In vitro approaches were used to screen the structural and activity effects of a range of potential ligands with purified VanSA protein. Of the screened ligands (glycopeptide antibiotics vancomycin and teicoplanin, and peptidoglycan components N-acetylmuramic acid, D-Ala-D-Ala and Ala-D-y-Glu-Lys-D-Ala-D-Ala) only glycopeptide antibiotics vancomycin and teicoplanin were found to bind VanSA with different affinities (vancomycin 70μM; teicoplanin 30 and 170μM), and were proposed to bind via exposed aromatic residues tryptophan and tyrosine. Furthermore, binding of the antibiotics induced quicker, longer-lived phosphorylation states for VanSA, proposing them as activators of type A vancomycin resistance in the enterococci. [Display omitted] •Vancomycin and teicoplanin (not peptidoglycan) are proposed as activating ligands.•Binding interaction involves tryptophan and tyrosine.•Binding results in increased phosphorylation activity for VanSA.