Membranes to Fight Drug-Resistant Microbes

A special issue of Antibiotics (ISSN 2079-6382). This special issue belongs to the section "Antimicrobial Peptides".

Deadline for manuscript submissions: 31 December 2024 | Viewed by 8997

Special Issue Editor


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Guest Editor
Institute of Molecular Biosciences, University of Graz, Humboldtstrasse 50/III, 8010 Graz, Austria
Interests: membrane-active compounds; antimicrobial peptides; anti-cancer peptides; lipid-peptide interactions; membrane-compound interaction; drug design

Special Issue Information

Dear Colleagues,

In the fight for finding possible ways to combat multidrug resistance, microbial membranes play a central role. Every microorganism is enveloped with a membrane, which gives them not only a unique character but protection that is essential for survival. The interruption of this fundamental barrier function leads to a rapid cell death and killing rate that is usually faster than the microbial growth rate. Such a non-specific mode of action is less likely to result in resistance and, amongst others, is effective on a variety of microbes, including bacteria, fungi, biofilms, and membrane-enveloped viruses. Compounds disrupting or acting on microbial membranes are generally termed as membrane-active and examples include antimicrobial peptides (AMPs), lipidoids, or many other small molecules, such as quaternary ammonium compounds. The mechanism behind the killing of microorganisms underlies specific interactions of those compounds with major constituents of microbial membranes, in particular with (phospho)lipids. As some of the constituents of microbial membranes induce a number of physiological reactions, including inflammation in humans, agents that neutralise microbial membrane constituents might have a promising immunomodulatory role. In addition to being a target for drug discovery as a therapy or prevention of microbial infections, microbial membranes are also attractive for development of immunization strategies, e.g., bacterial membrane vesicle as potential candidates for vaccines development. In this context, the scope of this Special Issue focuses on membranes as a target for drug/vaccine development and agents strongly affecting membrane architecture in diverse pathogens.

Dr. Nermina Malanovic
Guest Editor

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Keywords

  • antimicrobial peptides
  • membrane-active compounds
  • mode of action
  • lipidoids
  • vaccines

Published Papers (6 papers)

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Research

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9 pages, 772 KiB  
Communication
Impact of Interfering Substances on the Bactericidal Efficacy of Different Commercially Available Hypochlorous Acid-Based Wound Irrigation Solutions Commonly Found in South-East Asia
by Jiann Wen Yap, Neni Iffanida Ismail, Cheng Shoou Lee and Ding Yuan Oh
Antibiotics 2024, 13(4), 309; https://doi.org/10.3390/antibiotics13040309 - 28 Mar 2024
Viewed by 726
Abstract
The high prevalence of chronic wounds is a growing concern. Recently, hypochlorous acid (HOCl)-based solutions were introduced as an alternative antimicrobial for wound cleansing. In this study, we assessed the in vitro bactericidal activities of seven commercially available wound irrigation products commonly found [...] Read more.
The high prevalence of chronic wounds is a growing concern. Recently, hypochlorous acid (HOCl)-based solutions were introduced as an alternative antimicrobial for wound cleansing. In this study, we assessed the in vitro bactericidal activities of seven commercially available wound irrigation products commonly found in South-East Asia. The evaluation was conducted using quantitative suspension method, EN 13727 in either low or high protein conditions. Under low protein conditions, four out of the five HOCl products achieved bactericidal activity (≥5 log10 reduction factor; RF) within 2–5 min, and only one product achieved 5 log10 RF at 15 s. None of the HOCl achieved 5 log10 RF under high protein, even after 30 min of exposure time. In contrast, protein interference on the antimicrobial activities of polyhexamethylene biguanide-based product is less pronounced (low protein: 60 s vs. high protein: 2 min to attain ≥5 log10 RF). Octenidine dihydrochloride is the only active not affected by protein interference achieving ≥5 log10 RF within 15 s in both low and high protein conditions. These findings warrant the need to screen antimicrobial wound care products, especially HOCl-based products, in high protein condition to better reflect the antimicrobial activities in wound care. Full article
(This article belongs to the Special Issue Membranes to Fight Drug-Resistant Microbes)
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7 pages, 233 KiB  
Communication
Application of Octenidine into Nasal Vestibules Does Not Influence SARS-CoV-2 Detection via PCR or Antigen Test Methods
by Ojan Assadian, Fabiola Sigmund, Daniela Herzog, Karin Riedl and Christoph Klaus
Antibiotics 2023, 12(12), 1724; https://doi.org/10.3390/antibiotics12121724 - 13 Dec 2023
Viewed by 875
Abstract
The targeted or universal decolonization of patients through octenidine for nasal treatment and antiseptic body wash for 3 to 5 days prior elective surgery has been implemented in several surgical disciplines in order to significantly reduce surgical site infections (SSIs) caused by Staphylococcus [...] Read more.
The targeted or universal decolonization of patients through octenidine for nasal treatment and antiseptic body wash for 3 to 5 days prior elective surgery has been implemented in several surgical disciplines in order to significantly reduce surgical site infections (SSIs) caused by Staphylococcus aureus carriage. However, as most healthcare facilities also screen patients on admission for pilot infection, it is imperative that a prophylactic nasal decolonization procedure not yield a false negative SARS-CoV-2 status in otherwise positive patients. We assessed the effect of a commercially available octenidine-containing nasal gel on two different screening methods—antigen (Ag) detection based on colloidal gold immunochromatography and RT-PCR—in a prospective-type accuracy pilot study in asymptomatic SARS-CoV-2-positive inpatients. All patients still showed a positive test result after using the octenidine-containing nasal gel for about 3 days; therefore, its application did not influence SARS-CoV-2 screening, which is of high clinical relevance. Of note is that Ag detection was less sensitive, regardless of the presence of octenidine. From an infection prevention perspective, these results favor octenidine-based decolonization strategies, even during seasonal SARS-CoV-2 periods. As only asymptomatic patients are considered for elective interventions, screening programs based on RT-PCR technology should be preferred. Full article
(This article belongs to the Special Issue Membranes to Fight Drug-Resistant Microbes)
15 pages, 2710 KiB  
Article
Structure–Activity Relationships of Cationic Lipidoids against Escherichia coli
by James Jennings, Dunja Ašćerić, Nermina Malanovic and Georg Pabst
Antibiotics 2023, 12(8), 1300; https://doi.org/10.3390/antibiotics12081300 - 09 Aug 2023
Cited by 2 | Viewed by 883
Abstract
Membrane-active molecules provide a promising strategy to target and kill pathogenic bacteria. Understanding how specific molecular features drive interactions with membrane components and subsequently cause disruption that leads to antimicrobial activity is a crucial step in designing next-generation treatments. Here, we test a [...] Read more.
Membrane-active molecules provide a promising strategy to target and kill pathogenic bacteria. Understanding how specific molecular features drive interactions with membrane components and subsequently cause disruption that leads to antimicrobial activity is a crucial step in designing next-generation treatments. Here, we test a library of lipid-like compounds (lipidoids) against Gram-negative bacteria Escherichia coli to garner in-depth structure–activity relationships using antimicrobial assays. Modular lipidoid molecules were synthesized in high-throughput, such that we could analyze 104 compounds with variable combinations of hydrophobic tails and cationic headgroups. Antibacterial activity was strongly correlated to specific structural features, including tail hydrophobicity and headgroup charge density, and also to the overall molecular shape and propensity for self-assembly into curved liquid crystalline phases. Dye permeabilization assays showed that E. coli membranes were permeabilized by lipidoids, confirming their membrane-active nature. The reduced permeabilization, as compared to Gram-positive Bacillus subtilis, alludes to the challenge of permeabilizing the additional outer membrane layer of E. coli. The effect of headgroup solubility in gemini-type lipidoids was also demonstrated, revealing that a headgroup with a more hydrophilic spacer between amine groups had enhanced activity against B. subtilis but not E. coli. This provides insight into features enabling outer membrane penetration and governing selectivity between bacterial species. Full article
(This article belongs to the Special Issue Membranes to Fight Drug-Resistant Microbes)
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17 pages, 2669 KiB  
Article
Adsorption/Desorption of Cationic-Hydrophobic Peptides on Zwitterionic Lipid Bilayer Is Associated with the Possibility of Proton Transfer
by Lea Pašalić, Andreja Jakas, Barbara Pem and Danijela Bakarić
Antibiotics 2023, 12(7), 1216; https://doi.org/10.3390/antibiotics12071216 - 21 Jul 2023
Cited by 1 | Viewed by 1149
Abstract
Cell-penetrating peptides (CPPs) are short peptides built up from dominantly cationic and hydrophobic amino acid residues with a distinguished ability to pass through the cell membrane. Due to the possibility of linking and delivering the appropriate cargo at the desired location, CPPs are [...] Read more.
Cell-penetrating peptides (CPPs) are short peptides built up from dominantly cationic and hydrophobic amino acid residues with a distinguished ability to pass through the cell membrane. Due to the possibility of linking and delivering the appropriate cargo at the desired location, CPPs are considered an economic and less invasive alternative to antibiotics. Besides knowing that their membrane passage mechanism is a complex function of CPP chemical composition, the ionic strength of the solution, and the membrane composition, all other details on how they penetrate cell membranes are rather vague. The aim of this study is to elucidate the ad(de)sorption of arginine-/lysine- and phenylalanine-rich peptides on a lipid membrane composed of 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) lipids. DSC and temperature-dependent UV-Vis measurements confirmed the impact of the adsorbed peptides on thermotropic properties of DPPC, but in an inconclusive way. On the other hand, FTIR spectra acquired at 30 °C and 50 °C (when DPPC lipids are found in the gel and fluid phase, respectively) unambiguously confirmed the proton transfer between particular titratable functional groups of R5F2/K5F2 that highly depend on their immediate surroundings (DPPC or a phosphate buffer). Molecular dynamic simulations showed that both peptides may adsorb onto the bilayer, but K5F2 desorbs more easily and favors the solvent, while R5F2 remains attached. The results obtained in this work highlight the importance of proton transfer in the design of CPPs with their desired cargo, as its charge and composition dictates the possibility of entering the cell. Full article
(This article belongs to the Special Issue Membranes to Fight Drug-Resistant Microbes)
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20 pages, 5945 KiB  
Article
Bactericidal Activity to Escherichia coli: Different Modes of Action of Two 24-Mer Peptides SAAP-148 and OP-145, Both Derived from Human Cathelicidine LL-37
by Ayse Ön, Djenana Vejzovic, James Jennings, Lena Parigger, Robert A. Cordfunke, Jan Wouter Drijfhout, Karl Lohner and Nermina Malanovic
Antibiotics 2023, 12(7), 1163; https://doi.org/10.3390/antibiotics12071163 - 08 Jul 2023
Cited by 4 | Viewed by 1924
Abstract
OP-145 and SAAP-148, two 24-mer antimicrobial peptides derived from human cathelicidin LL-37, exhibit killing efficacy against both Gram-positive and Gram-negative bacteria at comparable peptide concentrations. However, when it comes to the killing activity against Escherichia coli, the extent of membrane permeabilization does [...] Read more.
OP-145 and SAAP-148, two 24-mer antimicrobial peptides derived from human cathelicidin LL-37, exhibit killing efficacy against both Gram-positive and Gram-negative bacteria at comparable peptide concentrations. However, when it comes to the killing activity against Escherichia coli, the extent of membrane permeabilization does not align with the observed bactericidal activity. This is the case in living bacteria as well as in model membranes mimicking the E. coli cytoplasmic membrane (CM). In order to understand the killing activity of both peptides on a molecular basis, here we studied their mode of action, employing a combination of microbiological and biophysical techniques including differential scanning calorimetry (DSC), zeta potential measurements, and spectroscopic analyses. Various membrane dyes were utilized to monitor the impact of the peptides on bacterial and model membranes. Our findings unveiled distinct binding patterns of the peptides to the bacterial surface and differential permeabilization of the E. coli CM, depending on the smooth or rough/deep-rough lipopolysaccharide (LPS) phenotypes of E. coli strains. Interestingly, the antimicrobial activity and membrane depolarization were not significantly different in the different LPS phenotypes investigated, suggesting a general mechanism that is independent of LPS. Although the peptides exhibited limited permeabilization of E. coli membranes, DSC studies conducted on a mixture of synthetic phosphatidylglycerol/phosphatidylethanolamine/cardiolipin, which mimics the CM of Gram-negative bacteria, clearly demonstrated disruption of lipid chain packing. From these experiments, we conclude that depolarization of the CM and alterations in lipid packing plays a crucial role in the peptides’ bactericidal activity. Full article
(This article belongs to the Special Issue Membranes to Fight Drug-Resistant Microbes)
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Review

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29 pages, 1188 KiB  
Review
The Two Faces of Bacterial Membrane Vesicles: Pathophysiological Roles and Therapeutic Opportunities
by Himadri B. Thapa, Stephan P. Ebenberger and Stefan Schild
Antibiotics 2023, 12(6), 1045; https://doi.org/10.3390/antibiotics12061045 - 14 Jun 2023
Viewed by 2732
Abstract
Bacterial membrane vesicles (MVs) are nanosized lipid particles secreted by lysis or blebbing mechanisms from Gram-negative and -positive bacteria. It is becoming increasingly evident that MVs can promote antimicrobial resistance but also provide versatile opportunities for therapeutic exploitation. As non-living facsimiles of parent [...] Read more.
Bacterial membrane vesicles (MVs) are nanosized lipid particles secreted by lysis or blebbing mechanisms from Gram-negative and -positive bacteria. It is becoming increasingly evident that MVs can promote antimicrobial resistance but also provide versatile opportunities for therapeutic exploitation. As non-living facsimiles of parent bacteria, MVs can carry multiple bioactive molecules such as proteins, lipids, nucleic acids, and metabolites, which enable them to participate in intra- and interspecific communication. Although energetically costly, the release of MVs seems beneficial for bacterial fitness, especially for pathogens. In this review, we briefly discuss the current understanding of diverse MV biogenesis routes affecting MV cargo. We comprehensively highlight the physiological functions of MVs derived from human pathogens covering in vivo adaptation, colonization fitness, and effector delivery. Emphasis is given to recent findings suggesting a vicious cycle of MV biogenesis, pathophysiological function, and antibiotic therapy. We also summarize potential therapeutical applications, such as immunotherapy, vaccination, targeted delivery, and antimicrobial potency, including their experimental validation. This comparative overview identifies common and unique strategies for MV modification used along diverse applications. Thus, the review summarizes timely aspects of MV biology in a so far unprecedented combination ranging from beneficial function for bacterial pathogen survival to future medical applications. Full article
(This article belongs to the Special Issue Membranes to Fight Drug-Resistant Microbes)
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