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.
Highlights
Increase of 50 percent or more (≥ 50%) in survival rate relative to the vehicle control group indicates significant anti-infective activity
Summary: The study objective was to evaluate the antimicrobial activity of test articles in a lung infection model with S. pneumoniae (ATCC® 6301TM)
An increase in survival rate of 50 percent or more ( ≥ 50%) of the treated animals relative to the vehicle group indicates significant antimicrobial activity
Summary
Studies performed at the University of Queensland were approved by the Molecular Biosciences Animal Ethics Committee. Human ethics approval from the University of Queensland Medical Research Ethics Committee was obtained for use of human blood for haemolysis studies. The solubility of test compounds and their recovery from the incubation matrix were confirmed prior to the metabolic assay. The metabolic stability assay was performed by incubating each test compound (1 μM) with human (Xenotech, Lot #1210057) and mouse (Xenotech, Lot #1110071) liver microsomes at 37 °C and 0.4 mg mL−1 protein concentration. Concentrations of each test compound in quenched samples were determined by ultra performance liquid chromatography mass spectrometry (UPLC-MS) (Waters/Micromass Xevo triple quadrupole mass spectrometer). Note: Due to the minimal degradation of test compounds in this assay, a metabolite search was not conducted. Increase of 50 percent or more (≥ 50%) in survival rate relative to the vehicle control group indicates significant anti-infective activity
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