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The Ebola delta peptide is an amphipathic, 40-residue peptide encoded by the Ebola virus, referred to as E40. The membrane-permeabilising activity of the E40 delta peptide has been demonstrated in cells and lipid vesicles suggesting the E40 delta peptide likely acts as a viroporin. The lytic activity of the peptide increases in the presence of anionic lipids and a disulphide bond in the C-terminal part of the peptide. Previous in silico work predicts the peptide to show a partially helical structure, but there is no experimental information on the structure of E40. Here, we use circular dichroism spectroscopy to report the secondary structure propensities of the reduced and oxidised forms of the E40 peptide in water, detergent micelles, and lipid vesicles composed of neutral and anionic lipids (POPC and POPG, respectively). Results indicate that the peptide is predominately a random coil in solution, and the disulphide bond has a small but measurable effect on peptide conformation. Secondary structure analysis shows large uncertainties and dependence on the reference data set and, in our system, cannot be used to accurately determine the secondary structure motifs of the peptide in membrane environments. Nevertheless, the spectra can be used to assess the relative changes in secondary structure propensities of the peptide depending on the solvent environment and disulphide bond. In POPC-POPG vesicles, the peptide transitions from a random coil towards a more structured conformation, which is even more pronounced in negatively charged SDS micelles. In vesicles, the effect depends on the peptide-lipid ratio, likely resulting from vesicle surface saturation. Further experiments with zwitterionic POPC vesicles and DPC micelles show that both curvature and negatively charged lipids can induce a change in conformation, with the two effects being cumulative. Electrostatic screening from Na+ ions reduced this effect. The oxidised form of the peptide shows a slightly lower propensity for secondary structure and retains a more random coil conformation even in the presence of PG-PC vesicles.

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Herein, we investigated the toxicity and membrane-permeabilizing capabilities of Lpt and Lpt-like peptides, belonging to type I toxin-antitoxin systems carried by plasmid DNA of Lacticaseibacillus strains. These 29 amino acid peptides are predicted to form α-helical structures with a conserved central hydrophobic sequence and differently charged hydrophilic termini. Like Lpt, the expression of Lpt-like in E. coli induced growth arrest, nucleoid condensation, and cell membrane damage, suggesting membrane interaction as the mode of action. The membrane permeabilization activity of both peptides was evaluated by using liposome leakage assays, dynamic light scattering, and CD spectroscopy. Lpt and Lpt-like showed liposome leakage activity, which did not lead to liposome disruption but depended on peptide concentration. Lpt was generally more effective than Lpt-like, probably due to different physical chemical properties. Leakage was significantly reduced in larger liposomes and increased with negatively charged PCPS liposomes, indicating that electrostatic interactions and membrane curvature influence peptide activity. Contrary to most membrane-active peptides, Lpt an Lpt-like progressively lost their α-helical structure upon interaction with liposomes. Our data are inconsistent with the formation of membrane-spanning peptide pores but support a mechanism relying on the transient failure of the membrane permeability barrier possibly through the formation of "lipid pores".

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Signal transduction and homeostasis are regulated by complex protein interactions in the intracellular environment. Therefore, the transportation of impermeable macromolecules (nucleic acids, proteins, and drugs) that control protein interactions is essential for modulating cell functions and therapeutic applications. However, macromolecule transportation across the cell membrane is not easy because the cell membrane separates the intra/extracellular environments, and the types of molecular transportation are regulated by membrane proteins. Cell-penetrating peptides (CPPs) are expected to be carriers for molecular transport. CPPs can transport macromolecules into cells through endocytosis and direct translocation. The transport mechanism remains largely unclear owing to several possibilities. In this review, we describe the methods for investigating CPP conformation, translocation, and cargo transportation using artificial membranes. We also investigated biomolecular transport across living cell membranes via CPPs. Subsequently, we show not only the biochemical applications but also the synthetic biological applications of CPPs. Finally, recent progress in biomolecule and nanoparticle transportation via CPPs into specific tissues is described from the viewpoint of drug delivery. This review provides the opportunity to discuss the mechanism of biomolecule transportation through these two platforms.

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Growing antibiotic resistance is rapidly threatening the efficacy of treatments for Gram-negative infections. Bicycle molecules, constrained bicyclic peptides from diverse libraries generated by bacteriophage display that bind with high affinity to a chosen target are a potential new class of antibiotics. The generally impermeable bacterial outer membrane currently limits the access of peptides to bacteria. The conjugation of membrane active peptides offers an avenue for outer membrane penetration. Here, we investigate which physicochemical properties of a specific membrane active peptide (MAP), derived from ixosin-B, could be tweaked to enhance the penetration of conjugates by generating multiple MAP-Bicycle conjugate variants. We demonstrate that charge and hydrophobicity are important factors, which enhance penetration and, therefore, antimicrobial potency. Interestingly, we show that induction of secondary structure, but not a change in amphipathicity, is vital for effective penetration of the Gram-negative outer membrane. These results offer insights into the ways vectors could be designed to deliver Bicycle molecules (and other cargos) through biological membranes.

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Antimicrobial resistance is becoming more prominent day after day due to a number of mechanisms by microbes, especially the sophisticated biological barriers of bacteria, especially in Gram-negatives. There, the lipopolysaccharides (LPS) layer is a unique component of the outer leaflet of the outer membrane which is highly impermeable and prevents antibiotics from passing passively into the intracellular compartments. Biodynamers, a novel class of dynamically bio-responsive polymers, may open new perspectives to overcome this particular barrier by accommodating various secondary structures and form supramolecular structures in such bacterial microenvironments. Generally, bio-responsive polymers are not only candidates as bio-active molecules against bacteria but also carriers via their interactions with the cargo. Based on their dynamicity, design flexibility, biodegradability, biocompatibility, and pH-responsiveness, we investigated the potential of two peptide-based biodynamers for improving antimicrobial drug delivery. By a range of experimental methods, we discovered a greater affinity of Arg-biodynamers for bacterial membranes than for mammalian membranes as well as an enhanced LPS targeting on the bacterial membrane, opening perspectives for enhancing the delivery of antimicrobials across the Gram-negative bacterial cell envelope. This could be explained by the change of the secondary structure of Arg-biodynamers into a predominant ß-sheet character in the LPS microenvironment, by contrast to the α-helical structure typically observed for most lipid membrane-permeabilizing peptides. In comparison to poly-L-arginine, the intrinsic antibacterial activity of Arg-biodynamers was nearly unchanged, but its toxicity against mammalian cells was >128-fold reduced. When used in bacterio as an antibiotic potentiator, however, Arg-biodynamers improved the minimum inhibitory concentration (MIC) against Escherichia coli by 32 times compared to colistin alone. Similar effect has also been observed in two stains of Pseudomonas aeruginosa. Arg-biodynamers may therefore represent an interesting option as an adjuvant for antibiotics against Gram-negative bacteria and to overcome antimicrobial resistance.

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Nanoparticles, including liposomes and lipid nanoparticles, have garnered global attention due to their potential applications in pharmaceuticals, vaccines, and gene therapies. These particles enable targeted delivery of new drug modalities such as highly active small molecules and nucleic acids. However, for widespread use of nanoparticle-based formulations, it is crucial to comprehensively analyze their characteristics to ensure both efficacy and safety, as well as enable consistent production. In this context, this review focuses on our research using atomic force microscopy (AFM) to study liposomes and lipid nanoparticles. Our work significantly contributes to the capability of AFM to measure various types of liposomes in an aqueous medium, providing valuable insights into the mechanical properties of these nanoparticles. We discuss the applications of this AFM technique in assessing the quality of nanoparticle-based pharmaceuticals and developing membrane-active peptides.

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Infections caused by Staphylococcus aureus (S. aureus) are increasing difficult to treat because this pathogen is easily resistant to antibiotics. However, the development of novel antibacterial agents with high antimicrobial activity and low frequency of resistance remains a huge challenge. Here, building on the coupling strategy, an adamantane moiety was linked to the membrane-active Ru-based structure and then developed three novel metalloantibiotics: [Ru(bpy)2(L)](PF6)2 (Ru1) (bpy = 2,2-bipyridine, L = amantadine modified ligand), [Ru(dmb)2(L)](PF6)2 (Ru2) (dmb = 4,4'-dimethyl-2,2'-bipyridine) and [Ru(dpa)2(L)](PF6)2 (Ru3), (dpa = 2,2'-dipyridylamine). Notably, complex Ru1 was identified to be the best candidate agent, showing greater efficacy against S. aureus than most of clinical antibiotics and low resistance frequencies. Mechanism studies demonstrated that Ru1 could not only increase the permeability of bacterial cell membrane and then caused the leakage of bacterial contents, but also promoted the production of reactive oxygen species (ROS) in bacteria. Importantly, complex Ru1 inhibited the biofilm formation, exotoxin secretion and increased the potency of some clinical used antibiotics. In addition, Ru1 showed low toxic in vivo and excellent anti-infective efficacy in two animal infection model. Thus, Ru-based metalloantibiotic bearing adamantane moiety are promising antibacterial agents, providing a certain research basis for the future antibiotics research.

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To clarify the damage of lipid bilayer region in bacterial cell membrane caused by antimicrobial peptides (AMPs) and antimicrobial compounds (AMCs), their interactions with giant unilamellar vesicles (GUVs) of various lipid compositions have been examined. The findings revealed two main causes for the leakage: nanopore formation in the membrane and burst of GUVs. Although GUV burst has been explained previously based on the carpet model, the supporting evidence is limited. In this review, to better clarify the mechanism of GUV burst by AMPs, AMCs, and other membrane-active peptides, we described current knowledge of the conditions, characteristics, and detailed processes of GUV burst and the changes in the shape of the GUVs during burst. We identified several physical factors that affect GUV burst, such as membrane tension, electrostatic interaction, structural changes of GUV membrane such as membrane folding, and oil in the membrane. We also clarified one of the physical mechanisms underlying the instability of lipid bilayers that are associated with leakage in the carpet model. Based on these results, we propose a mechanism underlying some types of GUV burst induced by these substances: the growth of a nanopore to a micropore, resulting in GUV burst.

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Photoisomerizable peptides are promising drug candidates in photopharmacology. While azobenzene- and diarylethene-containing photoisomerizable peptides have already demonstrated their potential in this regard, reports on the use of spiropyrans to photoregulate bioactive peptides are still scarce. This work focuses on the design and synthesis of a spiropyran-derived amino acid, (S)-2-amino-3-(6'-methoxy-1',3',3'-trimethylspiro-[2H-1-benzopyran-2,2'-indolin-6-yl])propanoic acid, which is suitable for the preparation of photoisomerizable peptides. The utility of this amino acid is demonstrated by incorporating it into the backbone of BP100, a known membrane-active peptide, and by examining the photoregulation of the membrane perturbation by the spiropyran-containing peptides. The toxicity of the peptides (against the plant cell line BY-2), their bacteriotoxicity (E. coli), and actin-auxin oscillator modulation ability were shown to be significantly dependent on the photoisomeric state of the spiropyran unit.

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Emerging resistance of fungal pathogens and challenges faced in drug development have prompted renewed investigations into novel antifungal lipopeptides. The antifungal lipopeptide AF3 reported here is a natural lipopeptide isolated and purified from Bacillus subtilis. The AF3 lipopeptide's secondary structure, functional groups, and the presence of amino acid residues typical of lipopeptides were determined by circular dichroism, Fourier transform infrared spectroscopy, and nuclear magnetic resonance spectroscopy. The lipopeptide's low minimum inhibitory concentrations (MICs) of 4-8 mg/L against several fungal strains demonstrate its strong antifungal activity. Biocompatibility assays showed that ~ 80% of mammalian cells remained viable at a 2 × MIC concentration of AF3. The treated Candida albicans cells examined by scanning electron microscopy, transmission electron microscopy, and atomic force microscopy clearly showed ultrastructural alterations such as the loss of the cell shape and cell membrane integrity. The antifungal effect of AF3 resulted in membrane permeabilization facilitating the uptake of the fluorescent dyes-acridine orange (AO)/propidium iodide (PI) and FUN-1. Using 1,6-diphenyl-1,3,5-hexatriene (DPH) and 4-(2-[6-(dioctylamino)-2-naphthalenyl] ethenyl)-1-(3-sulfopropyl) pyridinium inner salt (di-8-ANEPPS), we observed that the binding of AF3 to the membrane bilayer results in membrane disruption and depolarization. Flow cytometry analyses revealed a direct correlation between lipopeptide activity, membrane permeabilization (~ 75% PI uptake), and reduced cell viability. An increase in 2',7'-dichlorodihydrofluorescein diacetate (DCFH-DA) fluorescence demonstrates endogenous reactive oxygen species production. Lipopeptide treatment appears to induce late-stage apoptosis and alterations to nuclear morphology, suggesting that AF3-induced membrane damage may lead to a cellular stress response. Taken together, this study illustrates antifungal lipopeptide's potential as an antifungal drug candidate. KEY POINTS: • The studied lipopeptide variant AF3 displayed potent antifungal activity against C. albicans • Its biological activity was stable to proteolysis • Analytical studies demonstrated that the lipopeptide is essentially membranotropic and able to cause membrane dysfunction, elevated ROS levels, apoptosis, and DNA damage.

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Infections caused by Staphylococcus aureus, notably methicillin-resistant S. aureus (MRSA), pose treatment challenges due to its ability to tolerate antibiotics and develop antibiotic resistance. The former, a mechanism independent of genetic changes, allows bacteria to withstand antibiotics by altering metabolic processes. Here, a potent methylazanediyl bisacetamide derivative, MB6, is described, which selectively targets MRSA membranes over mammalian membranes without observable resistance development. Although MB6 is effective against growing MRSA cells, its antimicrobial activity against MRSA persisters is limited. Nevertheless, MB6 significantly potentiates the bactericidal activity of gentamicin against MRSA persisters by facilitating gentamicin uptake. In addition, MB6 in combination with daptomycin exhibits enhanced anti-persister activity through mutual reinforcement of their membrane-disrupting activities. Crucially, the "triple" combination of MB6, gentamicin, and daptomycin exhibits a marked enhancement in the killing of MRSA persisters compared to individual components or any double combinations. These findings underscore the potential of MB6 to function as a potent and selective membrane-active antimicrobial adjuvant to enhance the efficacy of existing antibiotics against persister cells. The molecular mechanisms of MB6 elucidated in this study provide valuable insights for designing anti-persister adjuvants and for developing new antimicrobial combination strategies to overcome the current limitations of antibiotic treatments.

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This review presents a comprehensive analysis of electric field distribution at the water-lipid membrane interface in the context of its relationship to various biochemical problems. The main attention is paid to the methodological aspects of bioelectrochemical techniques and quantitative analysis of electrical phenomena caused by the ionization and hydration of the membrane-water interface associated with the phase state of lipids. One of the objectives is to show the unique possibility of controlling changes in the structure of the lipid bilayer initiated by various membrane-active agents that results in electrostatic phenomena at the surface of lipid models of biomembranes-liposomes, planar lipid bilayer membranes (BLMs) and monolayers. A set of complicated experimental facts revealed in different years is analyzed here in order of increasing complexity: from the adsorption of biologically significant inorganic ions and phase rearrangements in the presence of multivalent cations to the adsorption and incorporation of pharmacologically significant compounds into the lipid bilayer, and formation of the layers of macromolecules of different types.

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Addressing the current antibiotic-resistance challenge would be aided by the identification of compounds with novel mechanisms of action. Epilancin 15X, a lantibiotic produced by Staphylococcus epidermidis 15 × 154, displays antimicrobial activity in the submicromolar range against a subset of pathogenic Gram-positive bacteria. S. epidermidis is a common member of the human skin or mucosal microbiota. We here investigated the mechanism of action of epilancin 15X. The compound is bactericidal against Staphylococcus carnosus as well as Bacillus subtilis and appears to kill these bacteria by membrane disruption. Structure-activity relationship studies using engineered analogs show that its conserved positively charged residues and dehydroamino acids are important for bioactivity, but the N-terminal lactyl group is tolerant of changes. Epilancin 15X treatment negatively affects fatty acid synthesis, RNA translation, and DNA replication and transcription without affecting cell wall biosynthesis. The compound appears localized to the surface of bacteria and is most potent in disrupting the membranes of liposomes composed of negatively charged membrane lipids in a lipid II independent manner. Epilancin 15X does not elicit a LiaRS response in B. subtilis but did upregulate VraRS in S. carnosus. Treatment of S. carnosus or B. subtilis with epilancin 15X resulted in an aggregation phenotype in microscopy experiments. Collectively these studies provide new information on epilancin 15X activity.

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Antimicrobial peptide buforin II translocates across the cell membrane and binds to DNA. Its sequence is identical to a portion of core histone protein H2A making it a highly charged peptide. Buforin II has a proline residue in the middle of its sequence that creates a helix-hinge-helix motif which has been found to play a key role in its ability to translocate across the cell membrane. To explore the structure-function relationship of this proline residue this study has replaced P11 with a meta-substituted azobenzene amino acid (Z). The resultant peptide, photobuforin II, retained the secondary structure and membrane activity of the naturally occurring peptide while gaining new spectroscopic properties. Photobuforin II can be isomerized from its trans to cis isomer upon irradiation with ultra-violet (UV) light and from its cis to trans isomer upon irradiation with visible (VL). Photobuforin II is also fluorescent with an emission peak at 390 nm. The intrinsic fluorescence of the peptide was used to determine binding to the membrane and to DNA. VL-treated photobuforin II has a 2-fold lower binding constant compared to UV-treated photobuforin and causes 11-fold more membrane leakage in 3:1 POPC:POPG vesicles. Photobuforin II provides insights into the importance of structure function relationships in membrane active peptides while also demonstrating that azobenzene can be used in certain peptide sequences to produce intrinsic fluorescence.

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Peptides released on frogs' skin in a stress situation represent their only weapon against micro-organisms and predators. Every species and even population of frog possesses its own peptidome being appropriate for their habitat. Skin peptides are considered potential pharmaceuticals, while the whole peptidome may be treated as a taxonomic characteristic of each particular population. Continuing the studies on frog peptides, here we report the peptidome composition of the Central Slovenian agile frog Rana dalmatina population. The detection and top-down de novo sequencing of the corresponding peptides was conducted exclusively by tandem mass spectrometry without using any chemical derivatization procedures. Collision-induced dissociation (CID), higher energy collision-induced dissociation (HCD), electron transfer dissociation (ETD) and combined MS3 method EThcD with stepwise increase of HCD energy were used for that purpose. MS/MS revealed the whole sequence of the detected peptides including differentiation between isomeric Leu/Ile, and the sequence portion hidden in the disulfide cycle. The array of the discovered peptide families (brevinins 1 and 2, melittin-related peptides (MRPs), temporins and bradykinin-related peptides (BRPs)) is quite similar to that of R. temporaria. Since the genome of this frog remains unknown, the obtained results were compared with the recently published transcriptome of R. dalmatina.

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In recent decades, bioactive peptides have been gaining recognition in various biomedical areas, such as intracellular drug delivery (cell-penetrating peptides, CPPs) or anti-infective action (antimicrobial peptides, AMPs), closely associated to their distinct mode of interaction with biological membranes. Exploiting the interaction of membrane-active peptides with diverse targets (healthy, tumoral, bacterial or parasitic cell membranes) is opening encouraging prospects for peptides in therapeutics. However, ordinary peptides formed by L-amino acids are easily decomposed by proteases in biological fluids. One way to sidestep this limitation is to use topoisomers, namely versions of the peptide made up of D-amino acids in either canonic (enantio) or inverted (retroenantio) sequence. Rearranging peptide sequences in this fashion provides a certain degree of native structure mimicry that, in appropriate contexts, may deliver desirable biological activity while avoiding protease degradation. In this review, we will focus on recent accounts of membrane-active topoisomeric peptides with therapeutic applications as CPP drug delivery vectors, or as antimicrobial and anticancer candidates. We will also discuss the most common modes of interaction of these peptides with their membrane targets.

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Membrane-active peptides (MAPs) possess unique properties that make them valuable tools for studying membrane structure and function and promising candidates for therapeutic applications. This review paper provides an overview of the fundamental aspects of MAPs, focusing on their membrane interaction mechanisms and potential applications. MAPs exhibit various structural features, including amphipathic structures and specific amino acid residues, enabling selective interaction with multiple membranes. Their mechanisms of action involve disrupting lipid bilayers through different pathways, depending on peptide properties and membrane composition. The therapeutic potential of MAPs is significant. They have demonstrated antimicrobial activity against bacteria and fungi, making them promising alternatives to conventional antibiotics. MAPs can selectively target cancer cells and induce apoptosis, opening new avenues in cancer therapeutics. Additionally, MAPs serve as drug delivery vectors, facilitating the transport of therapeutic cargoes across cell membranes. They represent a fascinating class of biomolecules with significant potential in basic research and clinical applications. Understanding their mechanisms of action and designing peptides with enhanced selectivity and efficacy will further expand their utility in diverse fields. Exploring MAPs holds promise for developing novel therapeutic strategies against infections, cancer, and drug delivery challenges.

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Chemotherapy-conjugated immunotherapy in clinical oncology conceptually resembles the combined effects of cytoreduction and immunostimulation in membrane targeted cell killings mediated by pore-forming proteins or host defense peptides. Of the similar concept, targeting cancer cell membrane using membrane active peptides is a hopeful therapeutic modality but had long been hindered from in vivo application. Here we report an enabling strategy of pre-opsonizing a membrane penetrating Ir-complexed octa-arginine peptide (iPep) with serum albumin via intrinsic amphipathicity-driven bimodal interactions into nanoparticles (NP). We found that NP triggered stress-mediated 4T1 cell oncosis which induced potent immunological activation, surpassing several well-known immunogenic medicines. Vested with albumin-enhanced in vivo tumor targeting specificity and pharmacokinetic properties, NP showed combined chemo to immunotherapies of s. c. tumors in mice, with decreased percentages of MDSC, Treg, M2-like macrophage and improved infiltration of CTLs in tumor site, caused complete regression of 4T1 and CT26 tumors, outperforming clinical medicines. In a challenging orthotopic breast cancer model, boost i. v. injections of NP acted as in situ tumor vaccine that drastically enhanced 4T1-specific cellular and humoral immunities to reverse disease progression. Thus, with combined effects of direct cytoreduction, immune activation and tumor vaccine, iPep-NP presents the promise and potential of a new modality of cancer medicine.

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We report facially amphiphilic bile acid-based antimicrobials with a broad spectrum of activity against both bacterial and fungal pathogens and negligible detrimental effects on mammalian cells. Two lead compounds eliminated dormant subpopulations of various bacterial species, unlike conventional antibiotics. The lead compounds were also effective in eradicating biofilms of methicillin-resistant Staphylococcus aureus (MRSA), Pseudomonas aeruginosa, and Candida albicans. Additionally, these compounds substantially inhibited the formation of fungal biofilms (C. albicans). Mechanistic investigations revealed the membrane-active nature and endogenous reactive oxygen species (ROS) induction ability of these compounds. Finally, no detectable resistance was developed by the bacterial strains against this class of membrane-targeting antimicrobials.

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The search for next-generation antibacterial compounds that overcome the development of resistance can be facilitated by identifying how to target the cell membrane of bacteria. Understanding the key molecular features that enable interactions with lipids and lead to membrane disruption is therefore crucial. Here, we employ a library of lipid-like compounds (lipidoids) comprising modular structures with tunable hydrophobic and hydrophilic architecture to shed light on how the chemical functionality and molecular shape of synthetic amphiphilic compounds determine their activity against bacterial membranes. Synthesized from combinations of 8 different polyamines as headgroups and 13 acrylates as tails, 104 different lipidoids are tested for activity against a model Gram-positive bacterial strain (Bacillus subtilis). Results from the combinatorial screening assay show that lipidoids with the most potent antimicrobial properties (down to 2 µM) have intermediate tail hydrophobicity (i.e., c log P values between 3 and 4) and lower headgroup charge density (i.e., longer spacers between charged amines). However, the most important factor appeared to be the ability of a lipidoid to self-assemble into an inverse hexagonal liquid crystalline phase, as observed by small-angle X-ray scattering (SAXS) analysis. The lipidoids active at lowest concentrations, which induced the most significant membrane damage during propidium iodide (PI) permeabilization assays, were those that aggregated into highly curved inverse hexagonal liquid crystal phases. These observations suggest that the introduction of strong curvature stress into the membrane is one way to maximize membrane disruption and lipidoid antimicrobial activity. Lipidoids that demonstrated the ability to furnish this phase consisted of either (i) branched or linear headgroups with shorter linear tails or (ii) cyclic headgroups with 4 bulky nonlinear tails. On the contrary, lipidoids previously observed to adopt disc-like conformations that pack into bicontinuous cubic phases were significantly less effective against B. subtilis. The discovery of these structure-property relationships demonstrates that it is not simply a balance of hydrophobic and hydrophilic moieties that govern membrane-active antibacterial activity, but also their intrinsic curvature and collective behavior.

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