Protein-inspired antibiotics active against vancomycin- and daptomycin-resistant bacteria

Abstract

The public health threat posed by a looming ‘post-antibiotic’ era necessitates new approaches to antibiotic discovery. Drug development has typically avoided exploitation of membrane-binding properties, in contrast to nature’s control of biological pathways via modulation of membrane-associated proteins and membrane lipid composition. Here, we describe the rejuvenation of the glycopeptide antibiotic vancomycin via selective targeting of bacterial membranes. Peptide libraries based on positively charged electrostatic effector sequences are ligated to N-terminal lipophilic membrane-insertive elements and then conjugated to vancomycin. These modified lipoglycopeptides, the ‘vancapticins’, possess enhanced membrane affinity and activity against methicillin-resistant Staphylococcus aureus (MRSA) and other Gram-positive bacteria, and retain activity against glycopeptide-resistant strains. Optimised antibiotics show in vivo efficacy in multiple models of bacterial infection. This membrane-targeting strategy has potential to ‘revitalise’ antibiotics that have lost effectiveness against recalcitrant bacteria, or enhance the activity of other intravenous-administered drugs that target membrane-associated receptors.

Renaissance of vancomycin: approaches for breaking antibiotic resistance in multidrug-resistant bacteria

“…One promising approach of modification combines the properties of lipophilic membrane anchors with cationic cell-penetrating peptides as an electrostatic effector, which is supposed to interact with the negatively charged bacterial cell wall ( Fig. 3a; Blaskovich et al 2018). Yarlagadda et al (2014) were able to show that a modification with a single cationic quaternary ammonium in combination with a lipophilic element at the same position can tremendously increase the antimicrobial potential of vancomycin against resistant strains (Fig.…”

Developments in Glycopeptide Antibiotics

“…92 Additional mechanisms of action beyond Lipid II binding and peptidoglycan inhibition are evident from membrane perturbation studies, which clearly demonstrate that the vancapticins also result in membrane disruption, presumably due to the insertion of the MIE component. 92 …”

“…90−92 These substituents are designed to selectively deliver the vancapticin molecule, containing the Lipid II-binding vancomycin substructure, to bacterial membranes. The MIE provides a general lipid anchoring group, and the positively charged EEPS interacts with the predominantly anionic components of the bacterial membranes.…”

“…Indeed, the combined modifications lead to over 100-fold increases in potency against MRSA, with both MIE and EEPS components required for maximum effect, e.g., 7b MRSA MIC = 0.003 μg/mL versus vancomycin MRSA MIC = 1 μg/mL. 92 Additional mechanisms of action beyond Lipid II binding and peptidoglycan inhibition are evident from membrane perturbation studies, which clearly demonstrate that the vancapticins also result in membrane disruption, presumably due to the insertion of the MIE component. 92 …”

“…For example, a single 25 mg/kg dose of compound 7a was equivalent to a single 200 mg/kg dose of vancomycin 1 , with a 6-log reduction compared to saline control at 24 h in a neutropenic mouse thigh infection model against MRSA. 92 …”