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The inner membrane of Gram-negative bacteria is a symmetric phospholipid bilayer that serves as the essential boundary of the cytoplasm, separating it from the periplasmic space [3]. It is primarily composed of phosphatidylethanolamine, phosphatidylglycerol, and cardiolipin, and it plays a central role in energy production by hosting the electron transport chain and ATP synthase [3]. This membrane is a critical therapeutic target for last-resort antibiotics, specifically the polymyxin class (e.g., Polymyxin B and Colistin), which are employed against multi-drug resistant pathogens like Pseudomonas aeruginosa and Acinetobacter baumannii [1]. These drugs disrupt the membrane's integrity through electrostatic and hydrophobic interactions, causing depolarization and the lethal leakage of intracellular components [1][2]. Despite their efficacy, targeting the inner membrane presents significant clinical challenges, as these agents often exhibit a narrow therapeutic index with notable risks of nephrotoxicity and neurotoxicity in patients [1]. The integrity of the inner membrane is vital for bacterial survival, as its disruption leads to the immediate cessation of metabolic activity and cell death [4]. In the context of infection, the inner membrane acts as a final barrier that antibiotics must either bypass or destroy to achieve bactericidal effects [1].
Disruption of membrane integrity, displacement of divalent cations, and induction of cytoplasmic leakage [1][2].
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