Outer membrane as a drug target for the treatment of GNB infections

Antimicrobial resistance among Gram-negative bacteria (GNB) poses a critical challenge to global public health. A key factor contributing to this resistance is their unique outer membrane (OM), which serves as a formidable barrier to many antibiotics, particularly hydrophobic and high-molecular-weight compounds. The OM not only limits drug permeability but also houses efflux pumps that actively expel antibiotics, reducing intracellular drug concentrations. This review provides a comprehensive overview of potential OM targets, including the OM protein complex, β-barrel assembly machinery (Bam), lipopolysaccharide transport, localisation of lipoproteins and lipid A precursor (Lpx) pathways, their roles and antibiotics approved to target these components. In addition, the review presents other non-antibiotic therapies targeting the bacterial OM, including antimicrobial peptides, peptidomimetics, bacteriophages, vaccines and antibody-based therapies.