Abstract
Melittin is one of the most studied α-helical cationic membrane disrupting peptides. It is the main component of bee venom, however it is considered an antimicrobial peptide for its ability to kill bacteria. Melittin is believed to act by opening large toroidal pores in the plasma membrane of the targeted cells/bacteria, although this is questioned by some authors. Little is known, however, about the molecular mechanism leading to this activity. In this study the mechanism of action of melittin was studied by dye leakage and quartz crystal microbalance fingerprinting analysis in biomimetic model membranes. The results revealed the existence of multiple stages in the membrane disrupting action with characteristic differences between different membrane types. In bacterial-mimetic (charged) lipid mixtures the viscoelastic fingerprints suggest a surface-acting mechanism, whereas in mammalian-mimetic (neutral) membranes melittin appears to penetrate the bilayer already at low concentrations. In domain-forming mixed membranes melittin shows a preference for the domain containing predominantly zwitterionic lipids. The results confirm membrane poration but are inconsistent with the insertion-to-toroidal pore pathway. Therefore hypotheses of the two membrane disrupting pathways were developed, describing the membrane disruption as either surface tension modulation leading to toroidal pore formation, or linear aggregation leading to fissure formation in the membrane.
Highlights
The emergence of bacterial resistance to conventional antibiotics is one of the most significant international health problems of our time that requires an urgent solution[1]
Melittin is a case study of membrane disrupting peptides; its potential for drug development can only be realized once its mechanism of action is fully understood, and its sequence is engineered in a way that it can selectively target bacteria
According to CD measurements melittin remains unfolded in aqueous solution, but becomes 68% α-helical when interacting with a DMPC bilayer; notably, the helicity is only 32% when cholesterol is mixed to the phospholipid[19], suggesting that mammalian cells are protected against lysis and melittin exhibits some degree of specificity towards bacterial membranes
Summary
The emergence of bacterial resistance to conventional antibiotics is one of the most significant international health problems of our time that requires an urgent solution[1]. Interesting are cationic α-helical AMPs that kill bacteria by disrupting their plasma membrane, offering a specific class of potential therapeutic agents that are complementary to existing antibiotics, and which bacteria may not be able to develop resistance toward[6,7]. The mechanism of action is based solely on a rearrangement of the lipid molecules around the peptides to breach the membrane integrity, such as forming a pore structure of a defined geometry[22,23,24]. Specifics of this process are challenging to obtain due to the molecular dimensions of the interacting structures[23,25]. Even ss-NMR cannot distinguish multiple, co-existing membrane-bound states of the peptide, and, given that it essentially averages over all present molecules of a given species, it requires very high peptide to lipid ratios to clearly show the effect of the peptide[42]
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