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The bacterial outer membrane (OM) is a specialized asymmetric lipid bilayer found exclusively in Gram-negative bacteria, serving as a critical permeability barrier that protects the cell from toxic environmental agents and antibiotics (1.1.2, 1.2.3). It consists of an inner leaflet of phospholipids and an outer leaflet primarily composed of lipopolysaccharide (LPS), which acts as a potent endotoxin and is essential for bacterial viability (1.2.1, 1.3.4). Embedded within this membrane are various outer membrane proteins (OMPs), including porins for nutrient transport and complex machinery like the β-barrel assembly machine (BAM) and the lipopolysaccharide transport (Lpt) system, which are responsible for membrane biogenesis (1.1.3, 1.3.1). In clinical settings, the OM is a major driver of antimicrobial resistance by restricting drug entry and housing multidrug efflux pumps (1.3.4, 1.4.4). Therapeutic targeting of OM components includes direct disruption by polymyxins or the inhibition of specific assembly proteins by novel agents like darobactin and murepavadin (1.3.1, 1.3.5). Because these components are unique to bacteria and absent in eukaryotic cells, they represent highly selective targets for the development of next-generation antibiotics (1.4.2, 1.4.3).
Direct disruption of the lipid bilayer, inhibition of lipopolysaccharide transport (LptD inhibition), inhibition of outer membrane protein assembly (BamA inhibition), inhibition of lipid A biosynthesis (LpxC inhibition), and competitive displacement of divalent cations (1.3.4, 1.3.5, 1.4.4).
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