Abstract
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.
Highlights
IntroductionVancomycin and related glycopeptide antibiotics (GPAs) target transpeptidase and transglycosylase activities by binding to the C-terminal D-Ala-D-Ala dipeptide of the muramyl pentapeptide of peptidoglycan precursor Lipid II which inhibit the final steps of bacterial cell wall biosynthesis
Vancomycin is a tricyclic glycopeptide which is used as a first-line treatment for complicated diseases including skin and blood infections, endocarditis, bone and joint infections and meningitis in addition to infections caused by methicillin-resistant Staphylococcus aureus [1]
Vancomycin and related glycopeptide antibiotics (GPAs) target transpeptidase and transglycosylase activities by binding to the C-terminal D-Ala-D-Ala dipeptide of the muramyl pentapeptide of peptidoglycan precursor Lipid II which inhibit the final steps of bacterial cell wall biosynthesis
Summary
Vancomycin and related glycopeptide antibiotics (GPAs) target transpeptidase and transglycosylase activities by binding to the C-terminal D-Ala-D-Ala dipeptide of the muramyl pentapeptide of peptidoglycan precursor Lipid II which inhibit the final steps of bacterial cell wall biosynthesis. Using model cell wall precursor peptides such as N-acetyl-D-Ala-DAla, binding studies in aqueous solution have established that for many glycopeptides, the formation of entropically favourable asymmetric, back-to-back homodimers of the antibiotic [10,11,12] is mediated by sugar-sugar recognition [12,13]. Dimerisation is suggested to enhance the activity of the antibiotic, and this is supported by in vitro studies showing dimerisation and binding of D-Ala–D-Ala are generally cooperative phenomena [15]. It has been proposed that the dimer binds two adjacent cell wall precursors and that binding to D-Ala–D-Ala at one site on the glycopeptide dimer anchors the dimer to the cell wall and thereby enhances the second binding event through the chelate effect resulting
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