The Structural Basis for Induction of VanB Resistance

Abstract

Because teicoplanin and vancomycin are the last line of defense for many bacterial infections, the emergence of resistance to glycopeptide antibiotics in enterococci and streptococci has aroused concern. Despite their similarity in terms of structure and mechanism of action, vancomycin induces the expression of genes that leads to bacterial resistance, and teicoplanin does not. We have used a combination of chemical and enzymatic methods to produce sets of vancomycin and teicoplanin analogues that allow us to consider whether the aglycon, the carbohydrate, or other parts of these molecules stimulate VanB resistance. We show that the teicoplanin and vancomycin aglycons are the structural elements that lead to induction of resistance. We think that lipid-containing analogues of vancomycin, like teicoplanin itself, circumvent resistance because the lipid chain changes the periplasmic distribution of the glycopeptide and, therefore, changes the biosynthetic step that it blocks.

Revisiting quorum sensing: Discovery of additional chemical and biological functions for 3-oxo- N -acylhomoserine lactones

“…Given that P. aeruginosa employs AHL 1 as the principal autoinducer and the known bactericidal activity of tetramic acids, we hypothesized that compound 4 could have a biological function in the context of bacterial viability. We were guided by the observation that lipid-substituted antibiotics have been shown to localize near the cell membrane of Gram-positive bacteria (10). Indeed, significant antibacterial activity was observed against all tested Gram-positive bacterial strains in the presence of 4 after overnight incubation (Table 2), whereas no toxicity was observed against P. aeruginosa or other tested Gram-negative bacteria (Fig.…”

Multivalent Antibiotics via Metal Complexes: Potent Divalent Vancomycins against Vancomycin-Resistant Enterococci

“…∆S conf correlates, however, to little enhancement of the activity of dimeric Vans against vancomycin-sensitive strains and the less resistant VRE (VanC), which has been observed in other systems of divalent Vans, 16,17,34 suggesting the enhancement of the activity of dimeric Vans may depend on the composition of peptidoglycan precursors produced by the strains. 43 …”

Vancomycin analogues active against vanA-resistant strains inhibit bacterial transglycosylase without binding substrate

“…We have previously made many glycopeptide derivatives containing lipid substituents at different positions, either on the aglycone or on the carbohydrates (7,(33)(34)(35)(36). We have found that the potency of most lipid-linked glycopeptides decreases dramatically when their peptide-binding pockets are damaged, implying that peptide binding is important for activity.…”