Vancomycin is a well-known glycopeptide antibiotic exerting its action by blocking cell wall biosynthesis of gram positive bacteria. It is widely used to treat severe infections when other antimicrobials have proved to be ineffective or unavailable. However, one of its limitations is the instability in aqueous solutions. Therefore, the discovery of vancomycin stabilizers could help to increase its importance as part of the antimicrobial therapeutic arsenal. A number of vancomycin crystal structures, frequently with co-crystallized ligands, are available in the protein data bank. Several low-molecular vancomycin ligands, such as N-acetylglycine and N-acetyl-D-alanine, have been shown to inhibit vancomycin degradation by direct binding to this antibiotic. Based on a 2D similarity search, structurally related ligands were selected and tested in-vitro to evaluate their vancomycin stabilizing potential in water-based solutions. Subsequently, in-silico studies including ligand- and structure-based pharmacophore modeling (Figure 1), docking and molecular dynamics were employed to yield more potential stabilizers as well as provide insights into the molecular mechanism of vancomycin stabilization. Based on in-silico results, new potential vancomycin ligands were experimentally tested on their stabilizing effects of the antibiotics. This study yielded several low molecular weight ligands with stabilizing properties on vancomycin in water-based solutions. Moreover, aside from having found structural derivatives of known ligands, some ligands had new structural scaffolds not previously observed for this purpose. Some of the suggested ligands bind to vancomycin in the same activity range as seen for N-acetyl-D-alanine.

Quest for vancomycin stabilizing agents exploiting manifold computational and experimental approaches

ACS Spring Meeting 2021

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.