A biophysical approach to daunorubicin interaction with model membranes: relevance for the drug's biological activity

Daunorubicin is extensively used in chemotherapy for diverse types of cancer. Over the years, evidence has suggested that the mechanisms by which daunorubicin causes cytotoxic effects are also associated with interactions at the membrane level. The aim of the present work was to study the interplay between daunorubicin and mimetic membrane models composed of different ratios of 1,2-dimyristoyl- sn -glycero- 3 -phosphocholine (DMPC), sphingomyelin (SM) and cholesterol (Chol). Several biophysical parameters were assessed using liposomes as mimetic model membranes. Thereby, the ability of daunorubicin to partition into lipid bilayers, its apparent location within the membrane and its effect on membrane fluidity were investigated. The results showed that daunorubicin has higher affinity for lipid bilayers composed of DMPC, followed by DMPC : SM, DMPC : Chol and lastly by DMPC : SM : Chol. The addition of SM or Chol into DMPC membranes not only increases the complexity of the model membrane but also decreases its fluidity, which, in turn, reduces the amount of anticancer drug that can partition into these mimetic models. Fluorescence quenching studies suggest a broad distribution of the drug across the bilayer thickness, with a preferential location in the phospholipid tails. The gathered data support that daunorubicin permeates all types of membranes to different degrees, interacts with phospholipids through electrostatic and hydrophobic bonds and causes alterations in the biophysical properties of the bilayers, namely in membrane fluidity. In fact, a decrease in membrane fluidity can be observed in the acyl region of the phospholipids. Ultimately, such outcomes can be correlated with daunorubicin's biological action, where membrane structure and lipid composition have an important role. In fact, the results indicate that the intercalation of daunorubicin between the phospholipids can also take place in rigid domains, such as rafts that are known to be involved in different receptor processes, which are important for cellular function.

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Asymmetric phospholipids impart novel biophysical properties to lipid bilayers allowing environmental adaptation

10.1101/2020.06.03.130450 ◽

2020 ◽

Author(s):

Paul Smith ◽

Dylan M. Owen ◽

Christian D. Lorenz ◽

Maria Makarova

Keyword(s):

Lipid Bilayers ◽

Mammalian Cells ◽

Yeast Species ◽

Membrane Lipid ◽

Head Group ◽

Biophysical Properties ◽

Biophysical Parameters ◽

Unsaturated Lipids ◽

Chain Acyl ◽

Dynamics Simulations

AbstractPhospholipids are a diverse group of biomolecules consisting of a hydrophilic head group and two hydrophobic acyl tails. The nature of the head and length and saturation of the acyl tails are important for defining the biophysical properties of lipid bilayers. It has recently been shown that the membranes of certain yeast species contain high levels of unusual asymmetric phospholipids, consisting of one long and one medium chain acyl moiety – a configuration not common in mammalian cells or other well studied model yeast species. This raises the possibility that structurally asymmetric phospholipids impart novel biophysical properties to the yeast membranes. Here, we use atomistic molecular dynamics simulations (MD) and environmentally-sensitive fluorescent membrane probes to characterize key biophysical parameters of membranes formed from asymmetric lipids for the first time. Interestingly, we show that saturated, but asymmetric phospholipids maintain membrane lipid order across a wider range of temperatures and do not require acyl tail unsaturation or sterols to maintain their properties. This may allow cells to maintain membrane fluidity even in environments which lack the oxygen required for the synthesis of unsaturated lipids and sterols.

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Micropatterned Model Membranes Composed of Polymerized and Fluid Lipid Bilayers

Biophysical Journal ◽

10.1016/j.bpj.2009.12.440 ◽

2010 ◽

Vol 98 (3) ◽

pp. 78a

Author(s):

Kenichi Morigaki

Keyword(s):

Lipid Bilayers ◽

Model Membranes

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A selective membrane-targeting repurposed antibiotic with activity against persistent methicillin-resistant Staphylococcus aureus

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1904700116 ◽

2019 ◽

Vol 116 (33) ◽

pp. 16529-16534 ◽

Cited By ~ 24

Author(s):

Wooseong Kim ◽

Guijin Zou ◽

Taylor P. A. Hari ◽

Ingrid K. Wilt ◽

Wenpeng Zhu ◽

...

Keyword(s):

Staphylococcus Aureus ◽

Membrane Fluidity ◽

Lipid Bilayers ◽

Therapeutic Agent ◽

Md Simulations ◽

Persister Cells ◽

Methicillin Resistant ◽

Bacterial Membranes ◽

Selective Membrane ◽

Mrsa Infection

Treatment of Staphylococcus aureus infections is complicated by the development of antibiotic tolerance, a consequence of the ability of S. aureus to enter into a nongrowing, dormant state in which the organisms are referred to as persisters. We report that the clinically approved anthelmintic agent bithionol kills methicillin-resistant S. aureus (MRSA) persister cells, which correlates with its ability to disrupt the integrity of Gram-positive bacterial membranes. Critically, bithionol exhibits significant selectivity for bacterial compared with mammalian cell membranes. All-atom molecular dynamics (MD) simulations demonstrate that the selectivity of bithionol for bacterial membranes correlates with its ability to penetrate and embed in bacterial-mimic lipid bilayers, but not in cholesterol-rich mammalian-mimic lipid bilayers. In addition to causing rapid membrane permeabilization, the insertion of bithionol increases membrane fluidity. By using bithionol and nTZDpa (another membrane-active antimicrobial agent), as well as analogs of these compounds, we show that the activity of membrane-active compounds against MRSA persisters positively correlates with their ability to increase membrane fluidity, thereby establishing an accurate biophysical indicator for estimating antipersister potency. Finally, we demonstrate that, in combination with gentamicin, bithionol effectively reduces bacterial burdens in a mouse model of chronic deep-seated MRSA infection. This work highlights the potential repurposing of bithionol as an antipersister therapeutic agent.

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Thermal properties of lipid bilayers derived from the transient heating regime of upconverting nanoparticles

Nanoscale ◽

10.1039/d0nr06989b ◽

2020 ◽

Vol 12 (47) ◽

pp. 24169-24176

Author(s):

Ana R. N. Bastos ◽

Carlos D. S. Brites ◽

Paola A. Rojas-Gutierrez ◽

Rute A. S. Ferreira ◽

Ricardo L. Longo ◽

...

Keyword(s):

Thermal Properties ◽

Lipid Bilayer ◽

Lipid Bilayers ◽

Experimental Approach ◽

Heating Regime ◽

Biophysical Properties ◽

Transient Heating

An experimental approach and associated model to derive the nanoscale thermal properties of a conformal lipid bilayer supported on an upconverting nanoparticle, and which yields fundamental biophysical properties of the lipid bilayer.

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Interaction of the cellular prion protein with raft-like lipid membranes

Biological Chemistry ◽

10.1515/bc.2007.010 ◽

2007 ◽

Vol 388 (1) ◽

pp. 79-89 ◽

Cited By ~ 10

Author(s):

Kerstin Elfrink ◽

Luitgard Nagel-Steger ◽

Detlev Riesner

Keyword(s):

Prion Protein ◽

Lipid Bilayers ◽

Analytical Ultracentrifugation ◽

Chinese Hamster ◽

Lipid Vesicles ◽

Cellular Prion Protein ◽

Model Membranes ◽

Degree Of Saturation ◽

Insertion Reaction ◽

Chip Surface

Abstract Conversion of the cellular isoform of the prion protein (PrPC) into the disease-associated isoform (PrPSc) plays a key role in the development of prion diseases. Within its cellular pathway, PrPC undergoes several posttranslational modifications, i.e., the attachment of two N-linked glycans and a glycosyl phosphatidyl inositol (GPI) anchor, by which it is linked to the plasma membrane on the exterior cell surface. To study the interaction of PrPC with model membranes, we purified posttranslationally modified PrPC from transgenic Chinese hamster ovary (CHO) cells. The mono-, di- and oligomeric states of PrPC free in solution were analyzed by analytical ultracentrifugation. The interaction of PrPC with model membranes was studied using both lipid vesicles in solution and lipid bilayers bound to a chip surface. The equilibrium and mechanism of PrPC association with the model membranes were analyzed by surface plasmon resonance. Depending on the degree of saturation of binding sites, the concentration of PrPC released from the membrane into aqueous solution was estimated at between 10-9 and 10-7 M. This corresponds to a free energy of the insertion reaction of -48 kJ/mol. Consequences for the conversion of PrPC to PrPSc are discussed.

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