The integrity of the bacterial membrane is essential for bacterial cell survival. Anionic phospholipids within bacterial membranes are surface exposed, whereas in mammalian cells they are largely sequestered to the cytoplasmic surface. This discrepancy provides an opportunity to selectively target bacterial membrane function with antimicrobial chemotherapy. Vancomycin, a prototypical glycopeptide antibiotic acting on membrane associated targets involved in peptidoglycan synthesis, disrupts cell wall synthesis but does perturb the membrane directly. Here, we demonstrate that conjugation of short peptidic motifs onto the C-terminus of vancomycin results in greatly enhanced membrane affinity leading to additional modes of action. The resulting compounds display potent activity against methicillin-resistant Staphylococcus aureus (MRSA), and vancomycin-resistant enterococci. Optimisation of drug-like properties led to antibiotics with a pharmacokinetics profile consistent with once daily dosing and excellent in vivo efficacy in multiple models of bacterial infection, demonstrating the effectiveness of this antibiotic revitalisation strategy.
The octapeptins and polymyxins are structurally similar cyclic heptapeptide natural products with potent activity against Gram-negative bacteria. Octapeptins are a “forgotten” class of antibiotics whereas polymyxins are used clinically as a last-resort option. Both are decorated with positively charged 2,4-diaminobutyric acid residues, enabling electrostatic interaction with the phosphate head groups of lipid A, a hydrophobic membrane anchor that is a constituent of lipopolysaccharide (LPS), the major structural component of the outer leaflet of the Gram-negative outer membrane. Polymyxin resistance often arises from modification of lipid A which reduces polymyxin affinity through electrostatic repulsion. Despite their structural similarity, octapeptins possess the unique ability to overcome polymyxin resistance, with no discernable cross resistance, making this class ideal for further development as a last-line therapy. We have capitalized on this distinction, demonstrating that this class can be modified to produce analogues with broader spectra of action and reduced nephrotoxic potential relative to polymyxin, whilst maintaining equivalent efficacy.