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The bacterial cell envelope, comprising the cytoplasmic (inner) membrane and, in Gram-negative bacteria, an additional outer membrane, serves as a critical protective barrier and metabolic hub (Silhavy et al., 2010, Cold Spring Harb Perspect Biol). The cytoplasmic membrane is a phospholipid bilayer responsible for essential processes such as nutrient transport, energy generation via the electron transport chain, and lipid biosynthesis (Epand et al., 2016, Biochim Biophys Acta). In Gram-negative species, the outer membrane contains lipopolysaccharides (LPS) and porins, acting as a selective permeability barrier against toxic compounds, including many antibiotics (Nikaido, 2003, Microbiol Mol Biol Rev). Drugs targeting these membranes, such as polymyxins and lipopeptides, typically act by disrupting the structural integrity or electrical potential of the lipid bilayers, leading to rapid cell death (Straus & Hancock, 2006, Biochim Biophys Acta). While highly effective against multi-drug resistant pathogens, these agents often face challenges regarding systemic toxicity due to similarities between bacterial and mammalian membrane components or off-target effects (Baron et al., 2016, Int J Antimicrob Agents). Resistance can also emerge through membrane remodeling or modifications to LPS, posing a significant challenge in treating multi-drug resistant infections.
Disruption of membrane integrity through binding to lipopolysaccharides or phospholipids, leading to pore formation, depolarization, and leakage of intracellular contents.
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