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Microbial membrane anionic components are a diverse set of negatively charged molecules, such as phosphatidylglycerol (PG), cardiolipin (CL), and lipopolysaccharides (LPS), that constitute the outer layers of bacteria and fungi (Malanovic & Lohner, 2016). These components are essential for maintaining membrane structural integrity, anchoring cell wall polymers, and regulating ion homeostasis (Zhang et al., 2021). The high density of these anionic molecules creates a strong negative surface charge that distinguishes microbial membranes from the zwitterionic membranes of mammalian cells, providing a basis for the selective toxicity of many antimicrobial agents (Yeaman & Yount, 2003). Therapeutic agents like daptomycin and polymyxins exploit these anionic sites through initial electrostatic attraction, which is often followed by hydrophobic insertion into the lipid bilayer (Brogden, 2005). This interaction leads to membrane depolarization, pore formation, and the leakage of essential intracellular contents, ultimately resulting in rapid cell death (Humphries et al., 2013). Targeting these components is a primary strategy for developing cationic antimicrobial peptides (AMPs) to combat multi-drug resistant pathogens, although microbes can develop resistance by modifying these targets to reduce their net negative charge (Trimble et al., 2016).
Electrostatic binding of cationic drugs to anionic membrane components leading to membrane disruption and depolarization.
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