INMdok (Leibniz Institute for New Materials)
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Menadione as Antibiotic Adjuvant Against P. aeruginosa: Mechanism of Action, Efficacy and Safety
Full text linkAntibiotic resistance in chronic lung infections caused by Pseudomonas aeruginosa requires alternative approaches to improve antibiotic efficacy. One promising approach is the use of adjuvant compounds that complement antibiotic therapy. This study explores the potential of menadione as an adjuvant to azithromycin against planktonic cells and biofilms of P. aeruginosa, focusing on its mechanisms of action and cytotoxicity in pulmonary cell models. Methods: The effect of menadione in improving the antibacterial and antibiofilm potency of azithromycin was tested against P. aeruginosa. Mechanistic studies in P. aeruginosa and AZMr-E. coli DH5α were performed to probe reactive oxygen species (ROS) production and bacterial membrane disruption. Cytotoxicity of antibacterial concentrations of menadione was assessed by measuring ROS levels and membrane integrity in Calu-3 and A549 lung epithelial cells. Results: Adding 0.5 µg/mL menadione to azithromycin reduced the minimum inhibitory concentration (MIC) by four-fold and the minimum biofilm eradication concentration (MBEC) by two-fold against P. aeruginosa. Adjuvant mechanisms of menadione involved ROS production and disruption of bacterial membranes. Cytotoxicity tests revealed that antibacterial concentrations of menadione (≤64 µg/mL) did not affect ROS levels or membrane integrity in lung cell lines. Conclusions: Menadione enhanced the efficacy of azithromycin against P. aeruginosa while exhibiting a favorable safety profile in lung epithelial cells at antibacterial concentrations. These findings suggest that menadione is a promising antibiotic adjuvant. However, as relevant data on the toxicity of menadione is sparse, further toxicity studies are required to ensure its safe use in complementing antibiotic therapy
Annual report 2024 / Leibniz Institute for New Materials
Full text linkDas INM blickt auf ein besonderes Jahr 2024 zurück. Wissenschaftliche Highlights wie die Entwicklung einer selbst-befeuchtenden Kontaktlinse gegen das Trockene-Augen-Syndrom, neue Technologien und Materialien zur Rückgewinnung von Lithium aus ausgedienten Batterien und Akkus oder der Einsatz von Tintenstrahldruckern für die Herstellung industrieller Perowskit-Silizium-Tandemsolarzellen zeigen einmal mehr die Vielfalt und Innovationskraft der Forschung am INM. Auch aus finanzieller Sicht war das Jahr erfolgreich. Die Drittmitteleinnahmen konnten weiterhinauf einem hohen Niveau gehalten werden. [...
Identification and heterologous expression of an NRPS biosynthetic gene cluster responsible for the production of the pyrazinones Ichizinone A, B and C
Full text linkPyrazinones are a growing family of microbial NRPS-derived natural products showing interesting biological activities. These compounds are characterized by the presence of either a di- or trisubstituted heterocyclic, nonaromatic 2(1 H)-pyrazinone core in their structure. The most commonly occurring disubstituted pyrazinone natural products are synthesized through a dipeptide intermediate, which is further cyclized to yield the pyrazinone moiety. Trisubstituted pyrazinones are seldom found in natural products, with JBIR56 and JBIR57, isolated from marine Streptomyces, being notable examples. In contrast to the simply organized disubstituted pyrazinones, JBIR56 and JBIR57 are syn-thesized as tetrapeptides with unnatural beta-amino acid residue involved in the for-mation of the pyrazinone moiety. Despite interesting structural features, biosynthetic routes leading to the production of these compounds have not been reported yet. Here we report the discovery of new members of trisubstituted pyrazinone family– tetrapeptides ichizinones A-C in Streptomyces sp. LV45-129. Through sequence analysis and heterologous expression, a biosynthetic gene cluster encoding ichizinone production was identified. Based on gene annotation and sequence homology, a biosynthetic model was suggested. The presented results provide insights into the biosynthesis of rare trisubstituted pyrazinone natural products
Valorizing Organic Waste: Selenium Sulfide Production Mediated by Sulfate-Reducing Bacteria
Full text linkSelenium sulfide, the active ingredient of traditional antidandruff shampoos, is industrially produced from selenium dioxide (SeO2) and hydrogen sulfide (H2S) under acidic conditions. This reaction can also be carried out with natural H2S and H2S generated by sulfate-reducing bacteria (SRB). These bacteria are robust and, by relying on their conventional growth medium, also thrive in “waste” materials, such as a mixture of cabbage juice and compost on the one side, and a mixture of spoiled milk and mineral water on the other. In these mixtures, SRB are able to utilize the DL-lactate and sulfate (SO42−) present naturally and produce up to 4.1 mM concentrations of H2S in the gas phase above a standard culture medium. This gas subsequently escapes the fermentation vessel and can be collected and reacted with SeO2 in a separate compartment, where it yields, for instance, pure selenium sulfide, therefore avoiding the need for any cumbersome workup or purification procedures. Thus “harvesting” H2S and similar (bio-)gases produced by the fermentation of organic waste materials by suitable microorganisms provides an elegant avenue to turn dirty waste into valuable clean chemical products of considerable industrial and pharmaceutical interest
Convective Assembly of a Particle Monolayer
No full textRecently, the steady-state process of convective assembly has emerged as a viable production route for colloidal monolayers. The present study models the regions of particle assembly: Region I comprises convective concentration of a particle suspension in a liquid below a meniscus, Region II comprises permeation of fluid through the dense particle monolayer, and Region III comprises capillary densification. For each region, the dominant physics and nondimensional groups are identified, and quantitative models are derived to describe the evolution of microstructure in terms of the main process parameters. The concentration profile within the assembly zone of Region I is predicted, including the role of a concentration-dependent diffusion constant and the shape of the meniscus. The fluid flow through the assembled monolayer is treated in Region II, along with a stability calculation to reveal that isolated particle clusters do not survive on top of the monolayer. The physics of capillary crystallization is addressed in Region III, with an emphasis on the density of cracks that emerge. The Peclet number and Capillary number both play important roles but in different regions of the assembly process
PEARL: Protein Eluting Alginate with Recombinant Lactobacilli
No full textEngineered living materials (ELMs) made of bacteria in hydrogels have shown considerable promise for therapeutic applications through controlled and sustained release of complex biopharmaceuticals at low costs and with reduced wastage. While most therapeutic ELMs useE. colidue to its large genetic toolbox, most live biotherapeutic bacteria in development are lactic acid bacteria due to native health benefits they offer. Among these, lactobacilli form the largest family of probiotics with therapeutic potential in almost all sites of the body with a microbiome. A major factor limiting the use of lactobacilli in ELMs is their limited genetic toolbox.In this study, we build upon our recent work to expand the genetic programmability of probioticLactiplantibacillus plantarumWCFS1 for protein secretion and encapsulate it in a simple, cost-effective, and biocompatible core-shell alginate bead to develop an ELM. We demonstrate the controlled release of recombinant proteins, even up to 14 days from this ELM, thereby terming it PEARL - Protein Eluting Alginate with Recombinant Lactobacilli. Notably, lactobacillus encapsulation offered benefits like bacterial containment, protein release profile stabilization, and metabolite-induced cytotoxicity prevention. These findings demonstrate the mutual benefits of combining recombinant lactobacilli with alginate for the controlled and sustained release of proteins
Nanoparticle interactions with mucosal barriers
Full text linkHuman pulmonary mucus represents a tenacious barrier for pulmonary drug administration. The design of an efficient inhalation therapy demands a detailed understanding of the mucus layer and well characterized mucus models for the investigation of the behavior of therapeutics in mucus. The developed strategies used to circumvent the mucus barrier should be evaluated in terms of efficacy and safety. The application of various microscopy techniques provided new insights revealing a non-porous, heterogenous and composite structure of mucus. Calu-3 in vitro mucus was characterized regarding mucins as macromolecules, small metabolites, biophysical properties and compared to human pulmonary ex vivo mucus providing valuable input in terms of the interpretation of data obtained using these models. Calu-3 in vitro mucus was employed for the investigation of the impact of mucus modulation, as a mucus penetration enhancing strategy on the protective function of mucus. Cytotoxicity assessment of the impact of probing model particles revealed that modulation led to a reduced protective function of mucus emphasizing the importance of safety assessment of therapy protocols involving mucus modulation.Der menschliche pulmonale Mukus stellt eine Barriere für die Verabreichung von Medikamenten in die Lunge dar. Die Entwicklung einer effizienten Inhalationstherapie erfordert ein detailliertes Verständnis der Mukusschicht und gut charakterisierte Mukusmodelle zur Untersuchung des Verhaltens von Therapeutika im Mukus. Die entwickelten Strategien zur Umgehung der Mukusbarriere sollten im Hinblick auf ihre Wirksamkeit und Sicherheit bewertet werden. Die Mukus-Struktur wurde mittels verschiedener Mikroskopietechniken untersucht. Die Ergebnisse zeigten eine nicht poröse, heterogene Komposit-Struktur des Mukus. Calu-3 in vitro Mukus wurde in Bezug auf Muzine als Makromoleküle, kleine Metabolite und biophysikalische Eigenschaften charakterisiert und mit menschlichem pulmonalem ex vivo Mukus verglichen. Diese Untersuchung lieferte wertvolle Erkenntnisse für die Interpretation der mit diesen Modellen gewonnenen Daten. Calu-3 in vitro Mukus wurde verwendet, um den Einfluss der Mukusmodulation als Strategie zur Verbesserung der Mukuspenetration auf die Schutzfunktion des Mukus zu untersuchen. Die Zytotoxizitätsanalyse der Auswirkung von Modellpartikeln ergab, dass die Modulation zu einer verringerten Schutzfunktion des Mukus führte. Diese Ergebnisse betonen die Bedeutung von Sicherheitsuntersuchungen bei der Entwicklung der Therapieprotokolle, die eine Modulation des Mukus umfassen
A Role for Finger Properties in Exploration and Perception of Softness
Full text linkIndividuals with more elastic, more hydrated or smaller fingers usually show better performance in several passive touch tasks. In active touch, people use different exploratory procedures when evaluating object properties, and tune their exploratory parameters. For example, they indent stimuli to assess softness and optimize their peak forces to get relevant information. In this study, we aim to understand whether finger pad size, elasticity and hydration affect individuals’ force-tuning and discrimination performance in active softness perception. Participants performed two softness tasks in two different sessions. In one session, hyaluronic acid was applied to their finger pads to soften it, in the other they received no treatment. We assessed individual elasticity and hydration values with cutometer and corneometer in each session, and measured finger pad size in three dimension by caliper. In each task, two pairs of stimuli were presented to the participants (Young’s Modulus: 41.5 vs. 45.0; 28.7 vs. 31.3 kPa) who chose the softer stimulus. In the restricted task, they could apply force only up to 2 Newton, whereas there was no force limit in the unconstrained task. We found that participants with smaller finger pad size exerted less force in the restricted task and participants with more hydrated and elastic fingers exerted less force in the unconstrained task. The force-tuning disappeared in the unconstrained task when treatment was applied. These results indicate that people employ strategies according to their finger parameters and to the availability of cues whereas adaptation to treatment is likely to need longer practice
Characterization of the Cubamyces Menziesii Terpenome
Full text linkLong‐lasting polypore fungi are significant producers of terpene cyclases of high interest for medicinal or biotechnological applications. Following the 1000 Fungal Genomes initiative launched by the Joint Genome Institute, the genome of Cubamyces (C.) menziesii and identified 18 genes encoding sesquiterpene cyclases (STCs) is explored. In a search for robust catalysts suitable for practical applications, the 18 codon‐optimized open reading frames are cloned and overproduced the C. menziesii STCs in Escherichia coli. In ten cases, the catalytically active enzyme is purified and tested with three chemically synthesized linear diphosphates: geranyl diphosphate, farnesyl diphosphate (FDP), and geranylgeranyl diphosphate. Only FDP proved to be a substrate for these 10 enzymes. The product specificity of all these enzymes is determined by (GC‐MS) gas chromatography mass spectrometry and (NMR) nuclear magnetic resonance analysis. Among the 10 enzymes, four produced a predominant compound, four yielded two main compounds, and the remaining two acted as a multiproduct catalysts. This work sheds light on the potential sesquiterpenes involved in the chemical ecology of the polypore C. menziesii and provides evidence for the potential of Polyporales fungi in the identification of new sesquiterpene cyclase activities
Maintaining Shell Disorder with Kinked or Branched Ligands Stabilizes Apolar Nanoparticles
Full text linkUnderstanding how nanoparticles form stable colloids is fundamental to their practical applications. Nonlinear ligands are known to increase the stability of nanoparticles in apolar solvents compared to shells of linear alkyl chains. Here, we reveal the molecular origin of this colloidal stability. We observe that even a single methyl side chain can suppress disorder–order transitions in the ligand shell, with double bonds or branches leading to drastic decreases in agglomeration temperature in such dispersions. Through a combination of temperature-dependent X-ray scattering and molecular dynamics simulations, we show that these simple structural modifications prevent ligand molecules from forming ordered bundles, maintaining shell disorder even at temperatures approaching solvent freezing. The absence of ligand order enhances colloidal stability by weakening attraction between the ligand shells via a combination of energetic and entropic factors. This mechanism extends dispersion stability by more than 100 K compared to linear ligands of equivalent length. Our findings provide a molecular-level explanation for the enhanced stability previously observed with branched and unsaturated ligands, offering an effective strategy for engineering nanoparticle dispersions that remain stable across broad temperature ranges