Over 3000 membrane-active antimicrobial peptides (AMPs) have been discovered, but only three of them have been approved by the U.S. Food and Drug Administration (FDA) for therapeutic applications, i.e., gramicidin, daptomycin and colistin. Of the three approved AMPs, daptomycin is a last-line-of-defense antibiotic for treating Gram-positive infections. However its use has already created bacterial resistance. To search for its substitutes that might counter the resistance, we need to understand its molecular mechanism. The mode of action of daptomycin appears to be causing bacterial membrane depolarization through ion leakage. Daptomycin forms a unique complex with calcium ions and phosphatidylglycerol molecules in membrane at a specific stoichiometric ratio: Dap₂Ca₃PG₂. How does this complex promote ion conduction across the membrane? We hope that biophysics of peptide-membrane interaction can answer this question. This review summarizes the biophysical works that have been done on membrane-active AMPs to understand their mechanisms of action, including gramicidin, daptomycin, and underdeveloped pore-forming AMPs. The analysis suggests that daptomycin forms transient ionophores in the target membranes. We discuss questions that remain to be answered.

已经发现了3000多种具有膜活性的抗菌肽（AMP），但其中只有3种已被美国食品和药物管理局（FDA）批准用于治疗用途，即短杆菌肽，达托霉素和大肠菌素。在三种批准的AMP中，达托霉素是用于治疗革兰氏阳性感染的最后一道防线抗生素。然而，其使用已经产生了细菌抗性。为了寻找可以抵抗这种抗性的替代品，我们需要了解其分子机制。达托霉素的作用方式似乎是通过离子泄漏引起细菌膜去极化。达托霉素以特定的化学计量比与膜中的钙离子和磷脂酰甘油分子形成独特的复合物：Dap ₂ Ca ₃ PG ₂。这种复合物如何促进跨膜的离子传导？我们希望肽膜相互作用的生物物理学能够回答这个问题。这篇综述总结了对膜活性AMP进行的生物物理工作，以了解其作用机理，包括短杆菌肽，达托霉素和不发达的成孔AMP。分析表明达托霉素在靶膜中形成瞬时离子载体。我们讨论仍有待回答的问题。