Full hydrodynamic reversibility of the weak dimerization of vancomycin and elucidation of its interaction with VanS monomers at clinical concentration

PHILLIPS-JONES, M.K., LITHGO, R., DINU, V., GILLIS, Richard, HARDING, J.E., ADAMS, G.G. and HARDING, S.E. (2017). Full hydrodynamic reversibility of the weak dimerization of vancomycin and elucidation of its interaction with VanS monomers at clinical concentration. Scientific reports, 7 (1): 12697.

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Abstract

The reversibility and strength of the previously established dimerization of the important glycopeptide antibiotic vancomycin in four different aqueous solvents (including a medically-used formulation) have been studied using short-column sedimentation equilibrium in the analytical ultracentrifuge and model-independent SEDFIT-MSTAR analysis across a range of loading concentrations. The change in the weight average molar mass M w with loading concentration was consistent with a monomer-dimer equilibrium. Overlap of data sets of point weight average molar masses M w(r) versus local concentration c(r) for different loading concentrations demonstrated a completely reversible equilibrium process. At the clinical infusion concentration of 5 mg.mL−1 all glycopeptide is dimerized whilst at 19 µg.mL−1 (a clinical target trough serum concentration), vancomycin was mainly monomeric (<20% dimerized). Analysis of the variation of M w with loading concentration revealed dissociation constants in the range 25-75 μM, commensurate with a relatively weak association. The effect of two-fold vancomycin (19 µg.mL−1) appears to have no effect on the monomeric enterococcal VanS kinase involved in glycopeptide resistance regulation. Therefore, the 30% increase in sedimentation coefficient of VanS on adding vancomycin observed previously is more likely to be due to a ligand-induced conformational change of VanS to a more compact form rather than a ligand-induced dimerization.

Item Type:	Article
Identification Number:	https://doi.org/10.1038/s41598-017-12620-z
SWORD Depositor:	Symplectic Elements
Depositing User:	Symplectic Elements
Date Deposited:	16 Dec 2022 15:13
Last Modified:	12 Oct 2023 08:32
URI:	https://shura.shu.ac.uk/id/eprint/31149

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