Antimicrobial resistance threatens the viability of modern medicine, which is largely dependent on the successful prevention and treatment of bacterial infections. Unfortunately, there are few new therapeutics in the clinical pipeline, particularly for Gram-negative bacteria. We now present a detailed evaluation of the antimicrobial activity of cannabidiol, the main non-psychoactive component of cannabis. We confirm previous reports of Gram-positive activity and expand the breadth of pathogens tested, including highly resistant Staphylococcus aureus, Streptococcus pneumoniae, and Clostridioides difficile. Our results demonstrate that cannabidiol has excellent activity against biofilms, little propensity to induce resistance, and topical in vivo efficacy. Multiple mode-of-action studies point to membrane disruption as cannabidiol’s primary mechanism. More importantly, we now report for the first time that cannabidiol can selectively kill a subset of Gram-negative bacteria that includes the ‘urgent threat’ pathogen Neisseria gonorrhoeae. Structure-activity relationship studies demonstrate the potential to advance cannabidiol analogs as a much-needed new class of antibiotics.

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.

D-Myrtoxin-Mp1a (Mp1a), a4 9-residue heterodimeric peptide from the venom of Myrmecia pilosula, comprises a2 6-mer Achain and a2 3-mer Bchain connected by two disulfide bonds in an antiparallel arrangement. Combination of the individual synthetic chains through aerial oxidation remarkably resulted in the self-assembly of Mp1a as ah omogenous product without the need for directed disulfide-bond formation. NMR analysis revealed aw ell-defined, unique structure containing an antiparallel a-helix pair.D ual polarization interferometry (DPI) analysis showed strong interaction with supported lipid bilayers and insertion within the bilayers.M p1a caused non-specific Ca 2+ influx in SH-SY5Y cells with ah alf maximal effective concentration (EC 50 )o f 4.3 mm.M p1a also displayed broad-spectrum antimicrobial activity,w ith the highest potency against Gram-negative Acinetobacter baumannii (MIC 25 nm). Intraplantar injection (10 mm)i nm ice elicited spontaneous pain and mechanical allodynia. Single-and two-chain mimetics of Mp1a revealed functional selectivity.

New antibiotics and innovative approaches to kill drug‐resistant bacteria are urgently needed. Metal complexes offer access to alternative modes of action but have only sparingly been investigated in antibacterial drug discovery. We have developed a light‐activated rhenium complex with activity against drug‐resistant S. aureus and E. coli. The activity profile against mutant strains combined with assessments of cellular uptake and synergy suggest two distinct modes of action.

For the first time Cu(0)-RDRP conditions were optimised to allow for the fast and controlled polymerisation of vinyl azlactone with tuneable lipid elements: a versatile platform material for the high-throughput synthesis of antimicrobial materials.