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Bacterial inner membrane anionic phospholipids, primarily phosphatidylglycerol and cardiolipin, are essential components of the bacterial cytoplasmic membrane that provide structural integrity and facilitate various biochemical processes (Epand et al., 2007). Unlike mammalian cell membranes, which are predominantly composed of neutral zwitterionic phospholipids, bacterial membranes are characterized by a high density of these negatively charged lipids. This distinct chemical property allows for the selective targeting of bacteria by cationic antimicrobial agents, such as daptomycin and polymyxins (Muller et al., 2016). These drugs interact with the anionic headgroups, leading to membrane insertion, depolarization, and the leakage of essential intracellular ions, which results in rapid cell death (Velkov et al., 2013). Beyond their role as a physical barrier, these phospholipids are involved in organizing the cell division machinery and maintaining the proton motive force necessary for ATP synthesis. As such, they are critical targets in the development of treatments for multi-drug resistant infections, although therapeutic use must account for potential off-target effects on host mitochondrial membranes which also contain cardiolipin.
Cationic antimicrobial agents bind to the negatively charged headgroups of anionic phospholipids via electrostatic interactions, followed by hydrophobic insertion into the lipid bilayer, which causes membrane depolarization, pore formation, and the leakage of intracellular contents such as potassium ions (Muller et al., 2016; Velkov et al., 2013).
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