A Redesigned Vancomycin Engineered for Dual d-Ala-d-Ala and d-Ala-d-Lac Binding Exhibits Potent Antimicrobial Activity Against Vancomycin-Resistant Bacteria

Abstract

The emergence of bacteria resistant to vancomycin, often the antibiotic of last resort, poses a major health problem. Vancomycin-resistant bacteria sense a glycopeptide antibiotic challenge and remodel their cell wall precursor peptidoglycan terminus from D-Ala-d-Ala to D-Ala-D-Lac, reducing the binding of vancomycin to its target 1000-fold and accounting for the loss in antimicrobial activity. Here, we report [Φ[C(=NH)NH]Tpg4]-vancomycin aglycon designed to exhibit the dual binding to D-Ala-D-Ala and D-Ala-D-Lac needed to reinstate activity against vancomycin-resistant bacteria. Its binding to a model D-Ala-D-Ala ligand was found to be only two-fold less than vancomycin aglycon and this affinity was maintained with a model D-Ala-D-Lac ligand, representing a 600-fold increase relative to vancomycin aglycon. Accurately reflecting these binding characteristics, it exhibits potent antimicrobial activity against vancomycin-resistant bacteria (MIC = 0.31 g/mL, VanA VRE). Thus, a complementary single atom exchange in the vancomycin core structure (O NH) to counter the single atom exchange in the cell wall precursors of resistant bacteria (NH O) reinstates potent antimicrobial activity and charts a rational path forward for the development of antibiotics for the treatment of vancomycin-resistant bacterial infections.

Substrate Inhibition of VanA by d -Alanine Reduces Vancomycin Resistance in a VanX-Dependent Manner

“…So far, attempts have included engineering VanX inhibitors (26,41,72) or reengineering vancomycin itself to target not only the cell wall precursors with D-Ala-D-Ala termini but also those ending with D-Ala-D-Lac (73). As a basis to develop new approaches to target vancomycin resistance, we studied the model organism S. coelicolor, which has a set of vancomycin resistance genes very similar to those of the pathogenic VRE (34).…”

Peripheral modifications of [Ψ[CH 2 NH]Tpg 4 ]vancomycin with added synergistic mechanisms of action provide durable and potent antibiotics

“…In a series of studies, we reported the first vancomycin analogs that contain changes at a key single-atom site in its target binding pocket (residue 4 carbonyl O → S, NH, H 2 ), the latter two of which were designed to directly address this underlying molecular basis of resistance to vancomycin ( Fig. 1) (43)(44)(45)(46)(47)(48)(49)(50). These rationally designed binding pocket modifications reinstated binding to the altered target D-Ala-D-Lac and maintained binding affinity for the unaltered target D-Ala-D-Ala.…”

Review of vancomycin-induced renal toxicity: an update

“…Similarly, synthesis of lipophilic vancomycin carbonhydrate analogs that exhibit greater than a 250-fold binding affinity against VanA and VanB strains of VRE has the potential of minimizing renal injury considerably [Yarlagadda et al 2015]. Furthermore, to overcome the reduction in the affinity produced by a resistant pathogen (by alteration of vancomycin binding site on cell wall), structural modification of the antibiotic for dual binding to D-Ala-d-Ala and D-Ala-D-Lac terminals has been designed [Xie et al 2011]. With the change in the ligand, there is a 600-fold increase in the binding strength relative to the native vancomycin compound.…”