1. Biochim Biophys Acta. 2013 May 17. pii: S0005-2736(13)00152-1. doi:
10.1016/j.bbamem.2013.05.006. [Epub ahead of print]

Surfactins modulate the lateral organization of fluorescent membrane polar
lipids: A new tool to study drug:membrane interaction and assessment of the role 
of cholesterol and drug acyl chain length.

D'Auria L, Deleu M, Dufour S, Mingeot-Leclercq MP, Tyteca D.

CELL Unit, de Duve Institute, UCL B1.75.02, Avenue Hippocrate, 75, B-1200
Brussels, Belgium; Université Catholique de Louvain, UCL B1.75.02, Avenue
Hippocrate, 75, B-1200 Brussels, Belgium.

The lipopeptide surfactin exhibits promising antimicrobial activities which are
hampered by haemolytic toxicity. Rational design of new surfactin molecules,
based on a better understanding of membrane:surfactin interaction, is thus
crucial. We here performed bioimaging of lateral membrane lipid heterogeneity in 
adherent living human red blood cells (RBCs), as a new relevant bioassay, and
explored its potential to better understand membrane:surfactin interactions. RBCs
show (sub)micrometric membrane domains upon insertion of BODIPY (*) analogs of
glucosylceramide (GlcCer*), sphingomyelin (SM*) and phosphatidylcholine (PC*).
These domains exhibit increasing sensitivity to cholesterol depletion by
methyl-β-cyclodextrin. At concentrations well below critical micellar
concentration, natural cyclic surfactin increased the formation of PC* and SM*,
but not GlcCer*, domains, suggesting preferential interaction with lipid*
assemblies with the highest vulnerability to methyl-β-cyclodextrin. Surfactin not
only reversed disappearance of SM* domains upon cholesterol depletion but further
increased PC* domain abundance over control RBCs, indicating that surfactin can
substitute cholesterol to promote micrometric domains. Surfactin sensitized
excimer formation from PC* and SM* domains, suggesting increased lipid*
recruitment and/or diffusion within domains. Comparison of surfactin congeners
differing by geometry, charge and acyl chain length indicated a strong dependence
on acyl chain length. Thus, bioimaging of micrometric lipid* domains is a visual 
powerful tool, revealing that intrinsic lipid* domain organization, cholesterol
abundance and drug acyl chain length are key parameters for membrane:surfactin
interaction. Implications for surfactin preferential location in domains or at
their boundaries are discussed and may be useful for rational design of better
surfactin molecules.

Copyright © 2013. Published by Elsevier B.V.

PMID: 23685123  [PubMed - as supplied by publisher]