Hidden complexity in membrane permeabilization behavior of antimicrobial polycations

Shi, Shuai; Quarta, Ndjali; Zhang, Haodong; Lu, Ziyi; Hof, Martin; Šachl, Radek; Liu, Runhui; Hoernke, Maria

doi:10.1039/d0cp05651k

Cited by 9 publications

(45 citation statements)

References 53 publications

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“…[81] However, there is no hydrodynamic radius drop even at the high concentration of C0-ionenes, which was also observed for other hydrophilic polycations. [32,82,83] Zeta-potential of LUVs covered with C0-D-PEG and C8-D-PEG is lower than for C0-D-m and C8-D-m, which remains in agreement with results reported for LUVs containing a small amount of PEGylated lipids. [81,84] Hemolytic activity of relatively hydrophilic ionenes is much lower than more hydrophobic ones (Table 2).…”

Section: The Studies On Model Bacterial Cell Membranessupporting

confidence: 88%

Influence of PEG Subunit on the Biological Activity of Ionenes: Synthesis of Novel Polycations, Antimicrobial and Toxicity Studies

Kopiasz

Kulbacka

Drężek

et al. 2022

Macromolecular Bioscience

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An alarming increase of antibiotic resistance among pathogens creates an urgent need to develop new antimicrobial agents. Many reported polycations show high antimicrobial activity along with low hemolytic activity. Unfortunately, most of those molecules remain highly cytotoxic against various mammalian cells. In this work, a systematic study on the impact of triethylene glycol monomethyl ether side groups (short polyethylene glycol (PEG) analog) on antimicrobial, hemolytic, and cytotoxic properties of novel amphiphilic ionenes is presented. A detailed description of synthesis, leading to well‐defined alternating polymers, which differ in structural elements responsible for hydrophilicity (PEG) and hydrophobicity (alkyl chain), is presented. Obtained results show that the PEG moiety and fine‐tuned hydrophilic‐lipophilic balance of ionenes synergistically lead to low cytotoxic, low hemolytic molecules with high activity against S. aureus, including methicillin‐resistant strains (MRSA). Additionally, the results of mechanistic studies on bacterial cells and fluorescently labeled liposomes are also discussed.

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Section: The Studies On Model Bacterial Cell Membranessupporting

confidence: 88%

Influence of PEG Subunit on the Biological Activity of Ionenes: Synthesis of Novel Polycations, Antimicrobial and Toxicity Studies

Kopiasz

Kulbacka

Drężek

et al. 2022

Macromolecular Bioscience

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“…27 POPE/ POPG vesicles are permeabilized by MM:CO by a transient effect. 23 The two most commonly discussed options, in this case, are asymmetric packing stress 28−31 or leaky vesicle fusion. 31 Indeed, MM:CO induced an increase in particle sizes, indicative of vesicle aggregation and/or fusion.…”

Section: ■ Introductionmentioning

confidence: 99%

“…31 Indeed, MM:CO induced an increase in particle sizes, indicative of vesicle aggregation and/or fusion. 23 Here, the reason for increased particle sizes is studied in more detail and MM:CO is established as a strong fusogen. Membrane leakage seems to be an independent mode of activity probably caused by asymmetric packing stress.…”

Section: ■ Introductionmentioning

confidence: 99%

“…Large unilamellar vesicles (LUVs) of POPE/POPG (1:1) with a diameter of ∼100 nm were prepared by the extrusion method as described. 23 For the preparation of PEG 2000vesicles, a determined amount of DSPE-PEG 2000 in chloroform was added to dry POPE/POPG (1:1) films. It was ensured that the lipid films were entirely and homogeneously dissolved and dried again to yield films of POPE/POPG/DSPE-PEG 2000 mixtures with a ratio of 50:50:1 or 50:50:4.…”

Section: ■ Introductionmentioning

confidence: 99%

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Interplay of Fusion, Leakage, and Electrostatic Lipid Clustering: Membrane Perturbations by a Hydrophobic Antimicrobial Polycation

Shi

Markl

et al. 2022

Langmuir

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Membrane active compounds are able to induce various types of membrane perturbations. Natural or biomimetic candidates for antimicrobial treatment or drug delivery scenarios are mostly designed and tested for their ability to induce membrane permeabilization, also termed leakage. Furthermore, the interaction of these usually cationic amphiphiles with negatively charged vesicles often causes colloidal instability leading to vesicle aggregation or/and vesicle fusion. We show the interplay of these modes of membrane perturbation in mixed phosphatidyl glycerol (PG)/phosphatidyl ethanolamine (PE) by the statistical copolymer MM:CO comprising, both, charged and hydrophobic subunits. MM:CO is a representative of partially hydrophobic, highly active, but less selective antimicrobial polycations. Cryo-electron microscopy indicates vesicle fusion rather than vesicle aggregation upon the addition of MM:CO to negatively charged PG/PE (1:1) vesicles. In a combination of fluorescence-based leakage and fusion assays, there is support for membrane permeabilization and pronounced vesicle fusion activity as distinct effects. To this end, membrane fusion and aggregation were prevented by including lipids with polyethylene glycol attached to their head groups (PEG-lipids). The leakage activity of MM:CO is very similar in the absence and presence of PEG-lipids. Vesicle aggregation and fusion however are largely suppressed. This strongly suggests that MM:CO induces leakage by asymmetric packing stress because of hydrophobically driven interactions which could lead to leakage. As a further membrane perturbation effect, MM:CO causes lipid clustering in model vesicles. We address potential artifacts and misinterpretations of experiments characterizing leakage and fusion. Additional to the leakage activity, the pronounced fusogenic activity of the polymer and potentially of many other similar compounds likely has implications for antimicrobial activity and beyond.

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“…The cell membranes of bacteria are negatively charged. Therefore, despite the use of antibiotics to destroy the genetic materials of bacteria, positively charged nanostructures usually showed antimicrobial activity due to the strong interaction with the cell membrane of bacteria [77][78][79][80][81]. Functionalization of positively charged molecules, such as AMPs and amines to the surface of polymer vesicles or using positively charged polymer chains as building blocks, are the main strategies to introduce positive charges to the surface of vesicles [82][83][84][85][86][87].…”

Section: Introduction Of Positively Charged Coronasmentioning

confidence: 99%

Polymer Vesicles for Antimicrobial Applications

2021

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Polymer vesicles, hollow nanostructures with hydrophilic cavity and hydrophobic membrane, have shown significant potentials in biomedical applications including drug delivery, gene therapy, cancer theranostics, and so forth, due to their unique cell membrane-like structure. Incorporation with antibacterial active components like antimicrobial peptides, etc., polymer vesicles exhibited enhanced antimicrobial activity, extended circulation time, and reduced cell toxicity. Furthermore, antibacterial, and anticancer can be achieved simultaneously, opening a new avenue of the antimicrobial applications of polymer vesicles. This review seeks to highlight the state-of-the-art of antimicrobial polymer vesicles, including the design strategies and potential applications in the field of antibacterial. The structural features of polymer vesicles, preparation methods, and the combination principles with antimicrobial active components, as well as the advantages of antimicrobial polymer vesicles, will be discussed. Then, the diverse applications of antimicrobial polymer vesicles such as wide spectrum antibacterial, anti-biofilm, wound healing, and tissue engineering associated with their structure features are presented. Finally, future perspectives of polymer vesicles in the field of antibacterial is also proposed.

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Hidden complexity in membrane permeabilization behavior of antimicrobial polycations

Abstract: There are diverse membrane permeabilization behaviors of antimicrobial polycations in zwitterionic or charged vesicles; different mechanisms may occur over time.

Cited by 9 publications

References 53 publications

Influence of PEG Subunit on the Biological Activity of Ionenes: Synthesis of Novel Polycations, Antimicrobial and Toxicity Studies

Influence of PEG Subunit on the Biological Activity of Ionenes: Synthesis of Novel Polycations, Antimicrobial and Toxicity Studies

Interplay of Fusion, Leakage, and Electrostatic Lipid Clustering: Membrane Perturbations by a Hydrophobic Antimicrobial Polycation

Polymer Vesicles for Antimicrobial Applications

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