scholarly journals The Optimal Lipid Chain Length of a Membrane-Permeabilizing Lipopeptide Results From the Balance of Membrane Partitioning and Local Damage

2021 ◽  
Vol 12 ◽  
Author(s):  
Jessica Steigenberger ◽  
Yentl Verleysen ◽  
Niels Geudens ◽  
José C. Martins ◽  
Heiko Heerklotz
Keyword(s):  
Chain Length ◽  
Acyl Chain ◽  
Local Perturbation ◽  
Spontaneous Curvature ◽  
Modes Of Action ◽  
Outer Leaflet ◽  
Membrane Partitioning ◽  
Lipid Chain ◽  
Calcein Release ◽  
Chain Lengths

Pseudodesmin A (PSD) is a cyclic lipodepsipeptide produced by Pseudomonas that kills certain bacteria at MIC1/2 in the single micromolar range, probably by permeabilizing their cellular membranes. Synthetic PSD variants, where the native decanoic (C10) acyl chain is varied in length from C4 to C8 and C12 to C14 carbons, were described to be not or less active against a panel of gram-positive strains, as compared to native PSD-C10. Here, we test the membrane-permeabilizing activity of PSD-C4 through PSD-C14 in terms of calcein release from liposomes, which is characterized in detail by the fluorescence-lifetime based leakage assay. Antagonistic concentrations and their chain length dependence agree well for liposome leakage and antimicrobial activity. The optimal chain length is governed by a balance between membrane partitioning (favoring longer chains) and the local perturbation or “damage” inflicted by a membrane-bound molecule (weakening for longer chains). Local perturbation, in turn, may involve at least two modes of action. Asymmetry stress between outer and inner leaflet builds up as the lipopeptides enter the outer leaflet and when it reaches a system-specific stability threshold, it causes a transient membrane failure that allows for the flip of some molecules from the outer to the inner leaflet. This cracking-in may be accompanied by transient, incomplete leakage from the aqueous cores of the liposomes observed, typically, for some seconds or less. The mismatch of the lipopeptide with the lipid leaflet geometry, expressed for example in terms of a spontaneous curvature, has two effects. First, it affects the threshold for transient leakage as described. Second, it controls the rate of equilibrium leakage proceeding as the lipopeptide has reached sufficient local concentrations in both leaflets to form quasi-toroidal defects or pores. Both modes of action, transient and equilibrium leakage, synergize for intermediate chain lengths such as the native, i.e., for PSD-C10. These mechanisms may also account for the reported chain-length dependent specificities of antibiotic action against the target bacteria.

scholarly journals Model and cell membrane partitioning of perfluorooctanesulfonate is independent of the lipid chain length

2010 ◽  
Vol 76 (1) ◽  
pp. 128-136 ◽  
Author(s):  
Wei Xie ◽  
Gabriele Ludewig ◽  
Kai Wang ◽  
Hans-Joachim Lehmler
Keyword(s):  
Cell Membrane ◽  
Chain Length ◽  
Membrane Partitioning ◽  
Lipid Chain

Acylcarnitine Chain Length Influences Carnitine-enhanced Drug Flux through the Spinal Meninges

1997 ◽  
Vol 86 (3) ◽  
pp. 642-648 ◽  
Author(s):  
Wolfgang C. Ummenhofer ◽  
Christopher M. Bernards
Keyword(s):  
Chain Length ◽  
Cell Model ◽  
Acyl Chain ◽  
Epidural Administration ◽  
Hydrophilic Drugs ◽  
Palmitoyl Carnitine ◽  
Before And After ◽  
Drug Flux ◽  
Chain Lengths

Background Palmitoyl carnitine has been shown to improve the penetration of hydrophilic drugs through the spinal meninges. Naturally occurring acylcarnitines, however, exist as a homologous series of different acyl chain lengths. The purpose of this study was to determine the most effective acylcarnitine chain length to increase meningeal permeability. Methods The transmeningeal flux of mannitol, morphine, and sufentanil through monkey spinal meninges was determined before and after adding acylcarnitines with chain lengths of 6 to 18 carbon atoms. Flux was measured using a previously established in vitro diffusion cell model. Results For mannitol, acylcarnitines generally showed a greater penetration-enhancing effect with increasing chain length, with palmitoyl carnitine (16 carbons) being the most effective compound with an increase of 244 +/- 29% (means +/- SE). Morphine flux was increased most significantly by lauroyl-(12 carbons) and myristoyl-carnitine (14 carbons) with 165 +/- 25% and 188 +/- 44% flux increases, respectively. In contrast, none of the studied acylcarnitines significantly altered the meningeal penetration of the more hydrophobic drug sufentanil. Conclusions The results suggest that, to promote hydrophilic drug penetration, acylcarnitines must surpass a critical chain length (10 carbon units) but should not exceed 16 carbon units. The activity of the acylcarnitines at the spinal meninges is reduced on either side of this range. The ability of acylcarnitines to increase the transmeningeal flux of morphine in vitro suggests that lauroyl or myristoyl carnitine may increase the spinal bioavailability of morphine after epidural administration.

scholarly journals Lipidation of Antimicrobial Peptides as a Design Strategy for Future Alternatives to Antibiotics

2020 ◽  
Vol 21 (24) ◽  
pp. 9692
Author(s):  
Taylor Rounds ◽  
Suzana K. Straus
Keyword(s):  
Antibacterial Activity ◽  
Chain Length ◽  
Bacterial Resistance ◽  
Acyl Chain ◽  
Resistant Bacteria ◽  
Host Defense Peptides ◽  
Acyl Chain Length ◽  
Natural Amino Acids ◽  
Chain Lengths ◽  
The Impact

Multi-drug-resistant bacteria are becoming more prevalent, and treating these bacteria is becoming a global concern. One alternative approach to combat bacterial resistance is to use antimicrobial (AMPs) or host-defense peptides (HDPs) because they possess broad-spectrum activity, function in a variety of ways, and lead to minimal resistance. However, the therapeutic efficacy of HDPs is limited by a number of factors, including systemic toxicity, rapid degradation, and low bioavailability. One approach to circumvent these issues is to use lipidation, i.e., the attachment of one or more fatty acid chains to the amine groups of the N-terminus or a lysine residue of an HDP. In this review, we examined lipidated analogs of 66 different HDPs reported in the literature to determine: (i) whether there is a link between acyl chain length and antibacterial activity; (ii) whether the charge and (iii) the hydrophobicity of the HDP play a role; and (iv) whether acyl chain length and toxicity are related. Overall, the analysis suggests that lipidated HDPs with improved activity over the nonlipidated counterpart had acyl chain lengths of 8–12 carbons. Moreover, active lipidated peptides attached to short HDPs tended to have longer acyl chain lengths. Neither the charge of the parent HDP nor the percent hydrophobicity of the peptide had an apparent significant impact on the antibacterial activity. Finally, the relationship between acyl chain length and toxicity was difficult to determine due to the fact that toxicity is quantified in different ways. The impact of these trends, as well as combined strategies such as the incorporation of d- and non-natural amino acids or alternative approaches, will be discussed in light of how lipidation may play a role in the future development of antimicrobial peptide-based alternatives to current therapeutics.

scholarly journals Intrinsic lipid curvatures of mammalian plasma membrane outer leaflet lipids and ceramides

2021 ◽  
Author(s):  
Michael Kaltenegger ◽  
Johannes Kremser ◽  
Moritz P. K. Frewein ◽  
Douwe J. Bonthuis ◽  
Primoz Ziherl ◽  
...  
Keyword(s):  
Saturated Hydrocarbon ◽  
Acyl Chain ◽  
Molecular Shape ◽  
Intrinsic Curvature ◽  
Membrane Function ◽  
Outer Leaflet ◽  
Hydrocarbon Chains ◽  
Unsaturated Acyl ◽  
Dynamics Simulations ◽  
Chain Lengths

We developed a global X-ray data analysis method to determine the intrinsic curvatures of lipids hosted in inverted hexagonal phases. In particular, we combined compositional modelling with molecular shape-based arguments to account for non-linear mixing effects of guest-in-host lipids on intrinsic curvature. The technique was verified by all-atom molecular dynamics simulations and applied to sphingomyelin and a series of phosphatidylcholines and ceramides with differing composition of the hydrocarbon chains. We report positive lipid curvatures for sphingomyelin and all phosphatidylcholines with disaturated and monounsaturated hydrocarbons. Substitution of the second saturated hydrocarbon with an unsaturated acyl chain in turn shifted the intrinsic lipid curvatures to negative values. All ceramides, with chain lengths varying between C2:0 and C24:0, displayed significant negative lipid curvature values. Moreover, we report non-additive mixing for C2:0 ceramide and sphingomyelin. Our findings manifest the high and manifold potential of lipids to modulate physiological membrane function.

scholarly journals Contribution of the Distal Pocket Residue to the Acyl-Chain-Length Specificity of (R)-Specific Enoyl-Coenzyme A Hydratases from Pseudomonas spp.

2015 ◽  
Vol 81 (23) ◽  
pp. 8076-8083 ◽  
Author(s):  
Takeharu Tsuge ◽  
Shun Sato ◽  
Ayaka Hiroe ◽  
Koya Ishizuka ◽  
Hiromi Kanazawa ◽  
...  
Keyword(s):  
Amino Acid ◽  
Substrate Specificity ◽  
Homology Modeling ◽  
Chain Length ◽  
Coenzyme A ◽  
Acyl Chain ◽  
Site Directed Mutagenesis ◽  
Content Type ◽  
Chain Length Specificity ◽  
Chain Lengths

ABSTRACT(R)-Specific enoyl-coenzyme A (enoyl-CoA) hydratases (PhaJs) are capable of supplying monomers from fatty acid β-oxidation to polyhydroxyalkanoate (PHA) biosynthesis. PhaJ1PpfromPseudomonas putidashowed broader substrate specificity than did PhaJ1PafromPseudomonas aeruginosa, despite sharing 67% amino acid sequence identity. In this study, the substrate specificity characteristics of twoPseudomonasPhaJ1 enzymes were investigated by site-directed mutagenesis, chimeragenesis, X-ray crystallographic analysis, and homology modeling. In PhaJ1Pp, the replacement of valine with isoleucine at position 72 resulted in an increased preference for enoyl-coenzyme A (CoA) elements with shorter chain lengths. Conversely, at the same position in PhaJ1Pa, the replacement of isoleucine with valine resulted in an increased preference for enoyl-CoAs with longer chain lengths. These changes suggest a narrowing and broadening in the substrate specificity range of the PhaJ1Ppand PhaJ1Pamutants, respectively. However, the substrate specificity remains broader in PhaJ1Ppthan in PhaJ1Pa. Additionally, three chimeric PhaJ1 enzymes, composed from PhaJ1Ppand PhaJ1Pa, all showed significant hydratase activity, and their substrate preferences were within the range exhibited by the parental PhaJ1 enzymes. The crystal structure of PhaJ1Pawas determined at a resolution of 1.7 Å, and subsequent homology modeling of PhaJ1Pprevealed that in the acyl-chain binding pocket, the amino acid at position 72 was the only difference between the two structures. These results indicate that the chain-length specificity of PhaJ1 is determined mainly by the bulkiness of the amino acid residue at position 72, but that other factors, such as structural fluctuations, also affect specificity.

Mechanisms of Drug Solubilization by Polar Lipids in Biorelevant Media

2020 ◽  
Author(s):  
Vladimir Katev ◽  
Zahari Vinarov ◽  
Slavka S. Tcholakova
Keyword(s):  
Chain Length ◽  
Acyl Chain ◽  
Polar Lipids ◽  
Superior Performance ◽  
Head Group ◽  
Formulation Development ◽  
Biorelevant Media ◽  
Drug Solubilization ◽  
Colloidal Aggregates ◽  
Class 1

Despite the widespread use of lipid excipients in both academic research and oral formulation development, rational selection guidelines are still missing. In the current study, we aimed to establish a link between the molecular structure of commonly used polar lipids and drug solubilization in biorelevant media. We studied the effect of 26 polar lipids of the fatty acid, phospholipid or monoglyceride type on the solubilization of fenofibrate in a two-stage <i>in vitro</i> GI tract model. The main trends were checked also with progesterone and danazol.<br>Based on their fenofibrate solubilization efficiency, the polar lipids can be grouped in 3 main classes. Class 1 substances (n = 5) provide biggest enhancement of drug solubilization (>10-fold) and are composed only by unsaturated compounds. Class 2 materials (n = 10) have an intermediate effect (3-10 fold increase) and are composed primarily (80 %) of saturated compounds. Class 3 materials (n = 11) have very low or no effect on drug solubilization and are entirely composed of saturated compounds.<br>The observed behaviour of the polar lipids was rationalized by using two classical physicochemical parameters: the acyl chain phase transition temperature (<i>T</i><sub>m</sub>) and the critical micellar concentration (CMC). Hence, the superior performance of class 1 polar lipids was explained by the double bonds in their acyl chains, which: (1) significantly decrease <i>T</i><sub>m</sub>, allowing these C18 lipids to form colloidal aggregates and (2) prevent tight packing of the molecules in the aggregates, resulting in bigger volume available for drug solubilization. Long-chain (C18) saturated polar lipids had no significant effect on drug solubilization because their <i>T</i><sub>m</sub> was much higher than the temperature of the experiment (<i>T</i> = 37 C) and, therefore, their association in colloidal aggregates was limited. On the other end of the spectrum, the short chain octanoic acid manifested a high CMC (50 mM), which had to be exceeded in order to enhance drug solubilization. When these two parameters were satisfied (C > CMC, <i>T</i><sub>m</sub> < <i>T</i><sub>exp</sub>), the increase of the polar lipid chain length increased the drug solubilization capacity (similarly to classical surfactants), due to the decreased CMC and bigger volume available for solubilization.<br>The hydrophilic head group also has a dramatic impact on the drug solubilization enhancement, with polar lipids performance decreasing in the order: choline phospholipids > monoglycerides > fatty acids.<br>As both the acyl chain length and the head group type are structural features of the polar lipids, and not of the solubilized drugs, the impact of <i>T</i><sub>m</sub> and CMC on solubilization by polar lipids should hold true for a wide variety of hydrophobic molecules. The obtained mechanistic insights can guide rational drug formulation development and thus support modern drug discovery pipelines.<br>

Mechanisms of Drug Solubilization by Polar Lipids in Biorelevant Media

2020 ◽  
Author(s):  
Vladimir Katev ◽  
Zahari Vinarov ◽  
Slavka S. Tcholakova
Keyword(s):  
Chain Length ◽  
Acyl Chain ◽  
Polar Lipids ◽  
Superior Performance ◽  
Head Group ◽  
Formulation Development ◽  
Biorelevant Media ◽  
Drug Solubilization ◽  
Colloidal Aggregates ◽  
Class 1

Despite the widespread use of lipid excipients in both academic research and oral formulation development, rational selection guidelines are still missing. In the current study, we aimed to establish a link between the molecular structure of commonly used polar lipids and drug solubilization in biorelevant media. We studied the effect of 26 polar lipids of the fatty acid, phospholipid or monoglyceride type on the solubilization of fenofibrate in a two-stage <i>in vitro</i> GI tract model. The main trends were checked also with progesterone and danazol.<br>Based on their fenofibrate solubilization efficiency, the polar lipids can be grouped in 3 main classes. Class 1 substances (n = 5) provide biggest enhancement of drug solubilization (>10-fold) and are composed only by unsaturated compounds. Class 2 materials (n = 10) have an intermediate effect (3-10 fold increase) and are composed primarily (80 %) of saturated compounds. Class 3 materials (n = 11) have very low or no effect on drug solubilization and are entirely composed of saturated compounds.<br>The observed behaviour of the polar lipids was rationalized by using two classical physicochemical parameters: the acyl chain phase transition temperature (<i>T</i><sub>m</sub>) and the critical micellar concentration (CMC). Hence, the superior performance of class 1 polar lipids was explained by the double bonds in their acyl chains, which: (1) significantly decrease <i>T</i><sub>m</sub>, allowing these C18 lipids to form colloidal aggregates and (2) prevent tight packing of the molecules in the aggregates, resulting in bigger volume available for drug solubilization. Long-chain (C18) saturated polar lipids had no significant effect on drug solubilization because their <i>T</i><sub>m</sub> was much higher than the temperature of the experiment (<i>T</i> = 37 C) and, therefore, their association in colloidal aggregates was limited. On the other end of the spectrum, the short chain octanoic acid manifested a high CMC (50 mM), which had to be exceeded in order to enhance drug solubilization. When these two parameters were satisfied (C > CMC, <i>T</i><sub>m</sub> < <i>T</i><sub>exp</sub>), the increase of the polar lipid chain length increased the drug solubilization capacity (similarly to classical surfactants), due to the decreased CMC and bigger volume available for solubilization.<br>The hydrophilic head group also has a dramatic impact on the drug solubilization enhancement, with polar lipids performance decreasing in the order: choline phospholipids > monoglycerides > fatty acids.<br>As both the acyl chain length and the head group type are structural features of the polar lipids, and not of the solubilized drugs, the impact of <i>T</i><sub>m</sub> and CMC on solubilization by polar lipids should hold true for a wide variety of hydrophobic molecules. The obtained mechanistic insights can guide rational drug formulation development and thus support modern drug discovery pipelines.<br>

Sign in / Sign up

Export Citation Format

Share Document