Surfactin-Triggered Small Vesicle Formation of Negatively Charged Membranes: A Novel Membrane-Lysis Mechanism

Abstract

The molecular mode of action of the lipopeptide SF with zwitterionic and negatively charged model membranes has been investigated with solid-state NMR, light scattering, and electron microscopy. It has been found that this acidic lipopeptide (negatively charged) induces a strong destabilization of negatively charged micrometer-scale liposomes, leading to the formation of small unilamellar vesicles of a few 10s of nanometers. This transformation is detected for very low doses of SF (Ri = 200) and is complete for Ri = 50. The phenomenon has been observed for several membrane mixtures containing phosphatidylglycerol or phosphatidylserine. The vesicularization is not observed when the lipid negative charges are neutralized and a cholesterol-like effect is then evidenced, i.e., increase of gel membrane dynamics and decrease of fluid membrane microfluidity. The mechanism for small vesicle formation thus appears to be linked to severe changes in membrane curvature and could be described by a two-step action: 1), peptide insertion into membranes because of favorable van der Waals forces between the rather rigid cyclic and lipophilic part of SF and lipid chains and 2), electrostatic repulsion between like charges borne by lipid headgroups and the negatively charged SF amino acids. This might provide the basis for a novel mode of action of negatively charged lipopeptides.

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“…This leads to a local increase in membrane curvature and the complete destabilization of the planar membrane, i.e. its direct lyses (Buchoux et al, 2008). All of the above findings were obtained in vitro on model monolayers or bilayers.…”

“…14, 16 and 18 carbon atoms (Bouffioux et al, 2007). On the other hand, the fact that lipid chains are in a fluid or gel phase does not appear to be important, in contrast to other antimicrobial peptides, such as melittin (Buchoux et al, 2008). There is still some uncertainty regarding the role played by the presence of a negative charge on the phospholipid polar head, which, according to Maget-Dana and Ptak (MagetDana & Ptak, 1995) gives rise to electrostatic shielding, preventing the peptide cycle of surfactin from coming close to the phospholipid headgroups.…”

“…The miscibility of surfactin with dipalmitoylated (DP) phospholipids decreases in the order phosphatidylcholine > phosphatidylethanolamine > phosphatidylserine (PC>PE>PS). These surfactin-phospholipid interactions are modulated by not only the volume of the phospholipid headgroups (Bouffioux et al, 2007), but also their electrostatic properties and shape (Buchoux et al, 2008). The inverted-cone conformation of surfactin tends to counterbalance the ability of cone-shaped phosphatidylethanolamine molecules to form a hexagonal phase, thereby promoting surfactin stabilization in the membrane.…”

Flexible loops of thread-like micelles are formed upon interaction of l-α-dimyristoyl-phosphatidylcholine with the biosurfactant surfactin as revealed by cryo-electron tomography

“…During the last decade great progress has also been achieved with regard to the visualization of lipid-biosurfactant aggregates using advanced TEM- [20,44,45] and AFM- [22][23][24][25]46] techniques. For example, similar results have been reported for the interaction of fengycins with phospholipid membranes [45].…”

Binding structure and kinetics of surfactin monolayer formed at the air/water interface to counterions: A molecular dynamics simulation study

“…The presenting results firstly demonstrate that both carboxyl groups are 342 accessible for counterions, but the carboxyl group in Glu1 has better ac- peptide moiety is reduced [43]. 374 It was presumed that the formation of surfactin-cation 1:1 complex, 375 in which a salt bridge between two carboxyl groups was mediated by 376 divalent counterion, accounted for the stronger strength of the binding 377 between ionized surfactin and divalent counterions [14].…”