Fungal Biofilm Formation Research Articles

Discovery of highly potent triazole derivatives with broad-spectrum antifungal activity based on Iodiconazole

The widespread use of broad-spectrum antibiotics, the growing number of immunocompromised individuals, and the emergence of drug-resistant strains have resulted in the increasing incidence and mortality of invasive fungal infections. Azole drugs are the primary treatment for invasive fungal infections, and Iodiconazole is a potent azole drug with strong antifungal activity, but its stability is poor. In order to improve stability, a series of triazole compounds containing ethynyl group were designed and synthesized. Most of the compounds showed strong inhibitory activity against pathogenic fungi, among which compound 20l showed excellent inhibitory activity against pathogenic fungi and drug-resistant fungi. Importantly, and the stability of 20l (T1/2 = 30.2 min) was obviously improved compared with Iodiconazole (T1/2 = 4.39 min). In addition, the preferred compound 20l can prevent fungal phase transition and the formation of fungal biofilm, and show satisfactory fungicidal activity. In addition, the compound 20l was almost non-toxic to mammalian HUVEC cell and 293T cell. In vivo pharmacokinetic studies showed that 20l had acceptable pharmacokinetic properties. These results strongly demonstrate that compound 20l was worth further investigation as a potential antifungal inhibitor.

Identification of novel and potent triazoles targeting CYP51 for antifungal: Design, synthesis, and biological study

Invasive fungal infections (IFIs) are emerging as a serious infectious disease worldwide. Due to the lack of effective antifungal drugs and serious drug resistance, the number of people with low immunity is increasing, leading to high morbidity and mortality. Azole drugs targeting CYP51 are widely used in the treatment of invasive fungal infections. By analyzing representative azole antifungal drugs, the characteristics of pharmacophore were summarized. The binding mode of lead compound Iodiconazole was analyzed, and it was found that the narrow hydrophobic cavity was not fully occupied. Therefore, a series of triazole compounds were designed and synthesized by fragment growth strategy. Most of the compounds showed strong inhibitory activity against pathogenic fungi, among which compound A33 showed excellent inhibitory activity against pathogenic fungi and drug-resistant strains. In addition, the preferred compound A33 can prevent fungal phase transition, the formation of fungal biofilm, and show satisfactory fungicidal activity. In addition, the compound A33 was almost non-toxic to mammalian HUVEC cell. These results strongly suggested that compound A33 was worth further investigation as a potential azole inhibitor.

Synthesis, Antimicrobial and Antibiofilm Activities of Silver(I) Complexes with N-Alkylbenzimidazole Derivatives and Their Molecular Docking Study

This study investigates the antimicrobial and antibiofilm potential of three silver(I) complexes derived from N-alkylbenzimidazole derivatives: bis[(Z)-1-styryl-benzimidazole]silver(I) nitrate (4), bis[(E)-1-styryl-benzimidazole]silver(I) nitrate (5), and bis(1-cinnamyl-benzimidazole)silver(I) nitrate (6). Detailed synthesis and characterization of these complexes are followed by assessments of their efficacy against Staphylococcus aureus, Enterococcus faecalis, Pseudomonas aeruginosa, Escherichia coli, and Candida albicans. Among the tested compounds, complex 6 exhibited the highest antimicrobial activity, with a minimal inhibitory concentration of 6 µmol/L against P. aeruginosa, and significant antibiofilm activity, achieving 67.72% inhibition at a concentration of 3 µmol/L. These interesting findings led us to conduct a molecular docking study to understand the mechanisms of action by investigating the interactions between the silver(I) complexes and some key protein targets involved in bacterial and fungal biofilm formation, including (p)ppGpp synthetase/hydrolases, FtsZ proteins, and pyruvate kinases. This comprehensive approach, combining experimental and computational analyses derived from N-alkylbenzimidazole derivatives, particularly complex 6, which exhibits remarkable efficacy against various pathogens, reveals promising therapeutic applications of these silver(I) complexes and advances our understanding of their potential mode of action against biofilm-associated infections.

Chelerythrine ameliorates Aspergillus fumigatus keratitis through suppressing the LOX-1/p38 MAPK signaling pathway

PurposeAspergillus fumigatus (A. fumigatus) keratitis is a type of infectious corneal disease that significantly impairs vision. The objective of this study is to evaluate the therapeutic potential of chelerythrine (CHE) on A. fumigatus keratitis. MethodsThe antifungal activity of CHE was assessed through various tests including the minimum inhibitory concentration test, scanning electron microscopy, transmission electron microscopy, propidium iodide uptake test and plate count. Neutrophil infiltration and activity were assessed using immunofluorescence staining and the myeloperoxidase test. RT-PCR, western blotting assay, and ELISA were performed to measure the expression levels of proinflammatory cytokines (IL-1β and IL-6), NF-E2-related factor (Nrf2), heme oxygenase-1 (HO-1), and lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1), as well as to determine the ratio of phosphorylated-p38 (p-p38) mitogen-activated protein kinase (MAPK) to p38 MAPK. ResultsIn vitro, CHE inhibited the growth of A. fumigatus conidia, reduced fungal hyphae survival, and prevented fungal biofilm formation. In vivo, CHE reduced the severity of A. fumigatus keratitis and exhibited an excellent anti-inflammatory effect by blocking neutrophil infiltration. Furthermore, CHE decreased the expression levels of proinflammatory cytokines and LOX-1 at both mRNA and protein levels, while also decreasing the p-p38 MAPK/p38 MAPK ratio. Additionally, CHE increased the expression levels of Nrf2 and HO-1. ConclusionCHE provides protection against A. fumigatus keratitis through multiple mechanisms, including reducing fungal survival, inducing anti-inflammatory effects, enhancing Nrf2 and HO-1 expression, and suppressing the signaling pathway of LOX-1/p38 MAPK.

Synthesis, characterization, and antifungal properties of chrome-doped hydroxyapatite thin films

The development of thin films of chromium-doped hydroxyapatite (20CrHAp) deposited on silicon substrate by the spin coating method was realized for the first time. A coherent investigation of the physicochemical properties of 20CrHAp thin films was also carried out for the first time. The obtained thin films were studied by various techniques such as, scanning electron microscopy (SEM), atomic force microscopy (AFM), Fourier transform infrared spectroscopy (FTIR) investigations and fractal analysis. By scanning electron microscopy (SEM) studies were obtained valuable information about the surface morphology of the 20CrHAp thin films. The zeta potential (ZP), Dynamic light scattering (DLS) and ultrasound measurements (US) were used in order to evaluate the stability of 20CrHAp suspension. The ratio between the hydrodynamic diameter obtained by DLS and the particle diameter obtained by SEM was 1.6. The SEM results on 20CrHAp thin films suggested that the sample possess a conglomerate of nanoparticles unevenly distributed on their surface. The surface morphology of the 20CrHAp thin films was studied with the aid of atomic force microscopy (AFM). The AFM topography of the 20CrHAp thin film's surface highlighted that the thin films present the morphology of a continuum deposited layer composed of non-uniform particle conglomerates. The presence of hydroxyapatite on the surface of silicium substrate was revealed by the results of Fourier transform infrared spectroscopy (FTIR) investigations. The antifungal evaluation of the 20CrHAp thin films was performed using Candida albicans 10,231 ATCC fungal strain. The antifungal assays results depicted that the 20CrHAp thin films inhibited the fungal biofilm formation. More than that, the results of the antifungal studies revealed that 20CrHAp thin films exhibited good inhibitory effects on the development of the fungal cells on their surface. Furthermore, our investigation delves into the realm of Minkowski Functionals and fractal/multifractal analysis as applied to the examined films. Our findings reveal that nanocomposite coatings containing 20CrHAp exhibit robust antifungal characteristics, suggesting their viability as a compelling solution for advancing antifungal devices in biomedical contexts.

Formation of filamentous fungal biofilms in water and the transformation of resistance to chlor(am)ine disinfection

Biofilms are composed of complex multi-species in nature, potentially threatening drinking water safety. In this work, the formation of single- and multi-species fungal biofilms formed by Aspergillus niger (A. niger) and Aspergillus flavus (A. flavus), and the inactivation of mature biofilms using chlor(am)ine were firstly investigated. Results revealed that the antagonistic interaction occurred between A. niger and A. flavus. Chloramination at 20 mg/L for 30 min achieved 74.74 % and 76.04 % inactivation of A. flavus and multi-species biofilm, which were 1.69- and 1.84-fold higher than that of chlorine at the same condition. However, no significant difference was observed in the inactivation of A. niger biofilm between chlorine and monochloramine disinfection due to the lower amount of extracellular polymeric substance produced by it (p > 0.05). The inactivation of biofilm by monochloramine fitted the Weibull model well. According to the Weibull model, the monochloramine resistance of biofilm were as follows: A. flavus > multi-species > A. niger biofilm. Besides, an increase in reactive oxygen levels, damage of cell membrane, and leakage of intracellular substances in biofilms were observed after chlor(am)ination. More intracellular polysaccharides and proteins were leaked in chloramination inactivation (p < 0.05). This study provides important implications for controlling fungal biofilm.

Impact of Zinc Oxide on the Development of Aspergillus-Induced Maxillary Sinusitis Rabbit Model.

Aspergillus fumigatus is commonly found in the airway and is associated with airway inflammatory diseases. Zinc oxide (ZO) is known to be an essential microelement that facilitates fungal survival, growth, and proliferation. This study aimed to investigate the impact of ZO on A. fumigatus-induced fungal sinusitis in rabbits. Twenty-eight New Zealand white rabbits were divided into four groups for this study. Group 1 (6 sides) was treated with intramaxillary phosphate buffer saline (PBS) served as the negative control, Group 2 (6 sides) received intramaxillary PBS and ZO, Group 3 (8 sides) was treated with intramaxillary A. fumigatus alone, and Group 4 (8 sides) treated with intramaxillary A. fumigatus with ZO. After 4 and 12 weeks, sinus mucosal cytokine and transcription factor expressions were determined. A histological analysis was performed to determine inflammatory cell infiltration, number of secretory cells, and mucosal thickness. Fungal biofilm formation was determined using confocal laser microscopy. The intramaxillary instillation of A. fumigatus conidia led to an increase in protein and mRNA expression of interleukin (IL)-1β and IL-8 in the maxillary sinus mucosa. They were associated with mitogen-activated protein kinase and activator protein-1. Furthermore, intramaxillary instillation of fungal conidia resulted in significant enhancement of inflammatory cell infiltration, epithelial thickening, and fungal biofilm formation. However, intramaxillary ZO did not have a significant impact on A. fumigatus-induced cytokine protein and mRNA expression, and inflammatory cell infiltration and epithelial thickness in sinonasal mucosa. While intramaxillary instillation of A. fumigatus increased mucosal inflammation, cytokine production, and biofilm formation, the intramaxillary application of ZO did not have a significant influence on inflammation in the maxillary sinus mucosa.

Mitigating candidiasis with acarbose by targeting Candida albicans α-glucosidase: in-silico, in-vitro and transcriptomic approaches

Biofilm-associated candidiasis poses a significant challenge in clinical settings due to the limited effectiveness of existing antifungal treatments. The challenges include increased pathogen virulence, multi-drug resistance, and inadequate penetration of antimicrobials into biofilm structures. One potential solution to this problem involves the development of novel drugs that can modulate fungal virulence and biofilm formation, which is essential for pathogenesis. Resistance in Candida albicans is initiated by morphological changes from yeast to hyphal form. This transition triggers a series of events such as cell wall elongation, increased adhesion, invasion of host tissues, pathogenicity, biofilm formation, and the initiation of an immune response. The cell wall is a critical interface for interactions with host cells, primarily through various cell wall proteins, particularly mannoproteins. Thus, cell wall proteins and enzymes are considered potential antifungal targets. In this regard, we explored α-glucosidase as our potential target which plays a crucial role in processing mannoproteins. Previous studies have shown that inhibition of α-glucosidase leads to defects in cell wall integrity, reduced adhesion, diminished secretion of hydrolytic enzymes, alterations in immune recognition, and reduced pathogenicity. Since α-glucosidase, primarily converts carbohydrates, our study focuses on FDA-approved carbohydrate mimic drugs (Glycomimetics) with well-documented applications in various biological contexts. Through virtual screening of 114 FDA-approved carbohydrate-based drugs, a pseudo-sugar Acarbose, emerged as a top hit. Acarbose is known for its pharmacological potential in managing type 2 diabetes mellitus by targeting α-glucosidase. Our preliminary investigations indicate that Acarbose effectively inhibits C. albicans biofilm formation, reduces virulence, impairs morphological switching, and hinders the adhesion and invasion of host cells, all at very low concentrations in the nanomolar range. Furthermore, transcriptomic analysis reveals the mechanism of action of Acarbose, highlighting its role in targeting α-glucosidase.

Mortar functionalized with silver nanoparticles for antifungal activity

Building materials are susceptible to fungus attack, leading to structural and aesthetic problems. Nanotechnology has enabled the development of innovative products with unique properties, including antimicrobial capabilities. Although the antimicrobial potential of AgNPs is already known, research on the application of AgNPs in cementitious materials and the behavior in prevention of fungal biofilm formation are still an extremely limited topic. Specifically, against the fungi presented in this paper there are no reports. In this work, two types of composites were formulated using AgNPs (108 μg/mL and 54 μg/mL) and tested against Aspergillus and Fusarium biofilms, fungi causing losses during grain storage. The AgNPs composites showed strong antifungal capacity, reaching up to 99 % reduction of Fusarium and 57 % of Aspergillus biofilms. The reduction in the amount of Fusarium biofilm (AgNPs 108 μg/mL) is proven by SEM images. No Ag leaching and interference in the mechanical properties of 54 μg/mL mortar were observed. Thus, a promising solution is presented for applications in agribusiness. And also, with a small 6.22 % increase in cost, this innovative mortar can contribute to mitigate post-harvest losses caused by fungal contamination. Its significant role in preserving the integrity and quality of stored grains contributes significantly to food security and sustainability.

Antimicrobial and anti-biofilm properties of oleuropein against Escherichia coli and fluconazole-resistant isolates of Candida albicans and Candida glabrata

BackgroundSide effects associated with antimicrobial drugs, as well as their high cost, have prompted a search for low-cost herbal medicinal substances with fewer side effects. These substances can be used as supplements to medicine or to strengthen their effects. The current study investigated the effect of oleuropein on the inhibition of fungal and bacterial biofilm in-vitro and at the molecular level.Materials and methodsIn this experimental study, antimicrobial properties were evaluated using microbroth dilution method. The effect of oleuropein on the formation and eradication of biofilm was assessed on 96-well flat bottom microtiter plates and their effects were observed through scanning electron microscopy (SEM). Its effect on key genes (Hwp1, Als3, Epa1, Epa6, LuxS, Pfs) involved in biofilm formation was investigated using the quantitative reverse transcriptase-polymerase chain reaction (RT-qPCR) method.ResultsThe minimum inhibitory concentration (MIC) and minimum fungicidal/bactericidal concentration (MFC/MBC) for oleuropein were found to be 65 mg/ml and 130 mg/ml, respectively. Oleuropein significantly inhibited biofilm formation at MIC/2 (32.5 mg/ml), MIC/4 (16.25 mg/ml), MIC/8 (8.125 mg/ml) and MIC/16 (4.062 mg/ml) (p < 0.0001). The anti-biofilm effect of oleuropein was confirmed by SEM. RT-qPCR indicated significant down regulation of expression genes involved in biofilm formation in Candida albicans (Hwp1, Als3) and Candida glabrata (Epa1, Epa6) as well as Escherichia coli (LuxS, Pfs) genes after culture with a MIC/2 of oleuropein (p < 0.0001).ConclusionsThe results indicate that oleuropein has antifungal and antibacterial properties that enable it to inhibit or destroy the formation of fungal and bacterial biofilm.

Plumbagin inhibits fungal growth, HMGB1/LOX-1 pathway and inflammatory factors in A. fumigatus keratitis.

To investigate the anti-inflammatory and antifungal effects of plumbagin (PL) in Aspergillus fumigatus (A. fumigatus) keratitis, the minimum inhibitory concentration (MIC), time-killing curve, spore adhesion, crystal violet staining, calcium fluoride white staining, and Propidium Iodide (PI) staining were employed to assess the antifungal activity of PL in vitro against A. fumigatus. The cytotoxicity of PL was assessed using the Cell Counting Kit-8 (CCK8). The impact of PL on the expression of HMGB1, LOX-1, TNF-α, IL-1β, IL-6, IL-10 and ROS in A. fumigatus keratitis was investigated using RT-PCR, ELISA, Western blot, and Reactive oxygen species (ROS) assay. The therapeutic efficacy of PL against A. fumigatus keratitis was assessed through clinical scoring, plate counting, Immunofluorescence and Hematoxylin-Eosin (HE) staining. Finally, we found that PL inhibited the growth, spore adhesion, and biofilm formation of A. fumigatus and disrupted the integrity of its cell membrane and cell wall. PL decreased IL-6, TNF-α, and IL-1β levels while increasing IL-10 expression in fungi-infected mice corneas and peritoneal macrophages. Additionally, PL significantly attenuated the HMGB1/LOX-1 pathway while reversing the promoting effect of Boxb (an HMGB1 agonist) on HMGB1/LOX-1. Moreover, PL decreased the level of ROS. In vivo, clinical scores, neutrophil recruitment, and fungal burden were all significantly reduced in infected corneas treated with PL. In summary, the inflammatory process can be inhibited by PL through the regulation of the HMGB-1/LOX-1 pathway. Simultaneously, PL can exert antifungal effects by limiting fungal spore adhesion and biofilm formation, as well as causing destruction of cell membranes and walls.

Mechanophysical and Anti-Adhesive Properties of a Nanoclay-Containing PMMA Denture Resin.

Poly(methyl methacrylate) (PMMA) is commonly used for dental dentures, but it has the drawback of promoting oral health risks due to oral bacterial adhesion. Recently, various nanoparticles have been incorporated into PMMA to tackle these issues. This study aims to investigate the mechanophysical and antimicrobial adhesive properties of a denture resin by incorporating of nanoclay into PMMA. Specimens were prepared by adding 0, 1, 2, and 4 wt % surface-modified nanoclay (Sigma) to self-polymerizing PMMA denture resin. These specimens were then evaluated using FTIR, TGA/DTG, and FE-SEM with EDS. Various mechanical and surface physical properties, including nanoindentation, were measured and compared with those of pure PMMA. Antiadhesion experiments were conducted by applying a Candida albicans (ATCC 11006) suspension to the surface of the specimens. The antiadhesion activity of C. albicans was confirmed through a yeast-wall component (mannan) and mRNA-seq analysis. The bulk mechanical properties of nanoclay-PMMA composites were decreased compared to those of pure PMMA, while the flexural strength and modulus met the ISO 20795-1 requirement. However, there were no significant differences in the nanoindentation hardness and elastic modulus. The surface energy revealed a significant decrease at 4 wt % nanoclay-PMMA. The antiadhesion effect of Candida albicans was evident along with nanoclay content in the nanocomposites and confirmed by the reduced attachment of mannan on nanoclay-PMMA composites. mRNA-seq analysis supported overall transcriptome changes in altering attachment and metabolism behaviors on the surface. The nanoclay-PMMA materials showed a lower surface energy as the content increased, leading to an antiadhesion effect against Candida albicans. These findings indicate that incorporating nanoclay into PMMA surfaces could be a valuable strategy for preventing the fungal biofilm formation of denture base materials.

Natural compounds from freshwater mussels disrupt fungal virulence determinants and influence fluconazole susceptibility in the presence of macrophages in Cryptococcus neoformans.

As the prevalence and severity of global fungal infections rise, along with an increasing incidence of antifungal resistance, new strategies to combat fungal pathogens and overcome resistance are urgently needed. Critically, our current methods to overcome fungal infections are limited and drive the evolution of resistance forward; however, an anti-virulence approach to disarm virulence factors of the pathogen and promote host cell clearance is promising. Here, we explore the efficacy of natural compounds derived from freshwater mussels against classical fungal virulence determinants, including thermotolerance, capsule production, stress response, and biofilm formation. We integrate our phenotypic discoveries with state-of-the-art mass spectrometry-based proteomics to identify mechanistic drivers of these antifungal properties and propose innovative avenues to reduce infection and support the treatment of resistant strains.

The Effectiveness of Silver Nanoparticles Mixed with Calcium Hydroxide against Candida albicans: An Ex Vivo Analysis.

The purpose of this study was to assess the antifungal activity of silver nanoparticles (AgNPs) in combination with calcium hydroxide (Ca(OH)2) against Candida albicans (C. albicans). AgNPs was mixed with pure Ca(OH)2 powder in an aqueous base. A standard suspension (1 × 108 bacterial cells/mL) of C. albicans was prepared in a 96-well plate and incubated on shaker at 37 °C in 100% humidity to allow fungal biofilm formation in infected dentin slices (n = 98). The minimum inhibitory concentration (MIC) and minimum fungicidal concentration (MFC) of AgNPs alone or with Ca(OH)2 were determined. The samples were separately placed in 24-well tissue culture plates and divided into three experimental groups (0.03, 0.04, and 0.06) and three control groups; negative (saline) and positive chlorhexidine gel and Ca(OH)2. Quantitative measurements of fungal activity by XTT colorimetric assay and qualitative measurements using confocal laser microscopy and scanning electron microscopy were performed. The cell viability of C. albicans in the experimental groups was significantly reduced compared to the negative control group. The combination of (AgNPs (0.04%) and Ca(OH)2) was the most potent against C. albicans. The findings demonstrated that combining silver nanoparticles with Ca(OH)2 was more effective against C. albicans biofilm compared to Ca(OH)2 alone, suggesting a combing effect.

Nature-Derived Gelatin-Based Antifungal Nanotherapeutics for combatting Candida albicans Biofilms.

Infections caused by fungi are emerging global health challenges that are exacerbated by the formation of fungal biofilms. Further challenges arise from environmental contamination with antifungal agents, which promotes environmental acquisition of antifungal resistance. We report the generation of an efficient, sustainable, all-natural antifungal nanotherapeutic based on the integration of an antimicrobial natural essential oil into a gelatin-based nanoemulsion platform. Carvacrol-loaded gelatin nanoemulsions penetrated Candida albicans biofilms, resulting in death of C. albicans cells in biofilms, and displayed selective biofilm elimination without harmful effects on fibroblast cells in a fungal biofilm-mammalian fibroblast co-culture model. Furthermore, the nanoemulsions degraded in the presence of physiologically relevant biomolecules, reducing the potential for environmental pollution and ecotoxicity. Overall, the sustainability, and efficacy of the described gelatin nanoemulsion formulation provides an environmentally friendly strategy for treating biofilm-associated fungal infections, including those caused by drug-resistant fungi.

Zeolitic Imidazolate Framework-8 Offers an Anti-Inflammatory and Antifungal Method in the Treatment of Aspergillus Fungal Keratitis in vitro and in vivo.

Fungal keratitis is a serious blinding eye disease. Traditional drugs used to treat fungal keratitis commonly have the disadvantages of low bioavailability, poor dispersion, and limited permeability. To develop a new method for the treatment of fungal keratitis with improved bioavailability, dispersion, and permeability. Zeolitic Imidazolate Framework-8 (ZIF-8) was formed by zinc ions and 2-methylimidazole linked by coordination bonds and characterized by Scanning electron microscopy (SEM), X-ray diffraction (XRD), and Zeta potential. The safety of ZIF-8 on HCECs and RAW 264.7 cells was detected by Cell Counting Kit-8 (CCK-8). Safety evaluation of ZIF-8 on mice corneal epithelium was conducted using the Draize corneal toxicity test. The effects of ZIF-8 on fungal growth, biofilm formation, and hyphae structure were detected by Minimal inhibit concentration (MIC), crystal violet staining, Propidium Iodide (PI) testing, and calcofluor white staining. The anti-inflammatory effects of ZIF-8 on RAW 246.7 cells were evaluated by Quantitative Real-Time PCR Experiments (qPCR) and Enzyme-linked immunosorbent assay (ELISA). Clinical score, Colony-Forming Units (CFU), Hematoxylin-eosin (HE) staining, and immunofluorescence were conducted to verify the therapeutic effect of ZIF-8 on C57BL/6 female mice with fungal keratitis. In vitro, ZIF-8 showed outstanding antifungal effects, including inhibiting the growth of Aspergillus fumigatus over 90% at 64μg/mL, restraining the formation of biofilm, and destroying cell membranes. In vivo, treatment with ZIF-8 reduced corneal fungal load and mitigated neutrophil infiltration in fungal keratitis, which effectively reduced the severity of keratitis in mice and alleviated the infiltration of inflammatory factors in the mouse cornea. In addition, ZIF-8 reduces the inflammatory response by downregulating the expression of pro-inflammatory cytokines TNF-α, IL-6, and IL-1β after Aspergillus fumigatus infection in vivo and in vitro. ZIF-8has a significant anti-inflammatory and antifungal effect, which provides a new solution for the treatment of fungal keratitis.

A self-assembling peptide inhibits the growth and function of fungi via a wrapping strategy.

Fungal infections contribute substantially to human morbidity and mortality. A particular concern is the high rate of mortality associated with invasive fungal infections, which often exceeds 50.0% despite the availability of several antifungal drugs. Herein, we show a self-assembling antifungal peptide (AFP), which is able to bind to chitin on the fungal cell wall and in situ form AFP nanofibers, wrapping fungi. As a result, AFP limits the proliferation of fungi, slows down the morphological transformation of biphasic fungi, and inhibits the adhesion of fungi to host cells and the formation of biofilms. Compared to the broad-spectrum antifungal fluconazole, AFP achieved a comparable inhibitory effect (MIC50 = 3.5 μM) on fungal proliferation. In addition, AFP significantly inhibited the formation of fungal biofilms with the inhibition rate of 69.6% at 1 μM, better than fluconazole (17.2% at 1 μM). In a skin infection model of mice, it was demonstrated that AFP showed significantly superior efficacy to fluconazole. In the systemic candidiasis mouse model, AFP showed similar efficacy to first-line antifungal amphotericin B (AmpB) and anidulafungin (AFG). This study provides a promising wrapping strategy for anti-fungal infection.

A cross-sectional study on occupational exposure to microorganisms, endotoxin, hydrogen sulfide, and dust during work at drilling waste treatment plants.

This cross-sectional study aims to obtain knowledge about workers' exposure to airborne dust, bacterial and fungal species, endotoxin, biofilm formation, and hydrogen sulfide (H2S) in drilling waste treatment plants. In total, 408 full-shift personal samples, 66 work areas, 40 drilling waste, and reference (outdoor air and seawater) samples were analyzed. Some workers were exposed to high levels of endotoxin (207 EU/m3), bacteria (3.8 × 104 colony forming units (CFU)/m3 and 9.8 × 104 DNA copies/m3), or fungi (1.4 × 107 CFU/m3 and 3,600 copies/m3). The exposure levels to endotoxin, bacteria, and peaks of H2S were dependent on the treatment technique. All types of drilling waste contained large concentrations of bacteria compared to the seawater references. Elevated concentrations of airborne bacteria were found close to drilling waste basins. In total, 116, 146, and 112 different bacterial species were found in workers' exposure, work areas, and the drilling waste, respectively. An overlap in bacterial species found in the drilling waste and air (personal and work area) samples was found. Of the bacterial species found, 49 are classified as human pathogens such as Escherichia coli, Enterobacter cloacae, and Klebsiella oxytoca. In total, 44 fungal species were found in the working environment, and 6 of these are classified as human pathogens such as Aspergillus fumigatus. In conclusion, across the drilling waste treatment plants, human pathogens were present in the drilling waste, and workers' exposure was affected by the drilling waste treated at the plants with elevated exposure to endotoxin and bacteria. Elevated exposure was related to working as apprentices or chemical engineers, and working with cleaning, or slop water, and working in the daytime.

Antimicrobial and Antibiofilm Activities of Copper(II)-1,10-phenanthroline-5,6-pione Against Commensal Bacteria and Fungi Responsible for Vaginal Microbiota Dysbiosis.

The disbalance of vaginal eubiotic microbiota can lead to overgrowth of Candida species and bacteria responsible for aerobic vaginitis, activating inflammatory pathways. The presence of Trichomonas vaginalis, a sexually transmitted protozoan pathogen, can be a predisposing factor for disordering the growth of bacterial/fungal pathogenic species due to the increase in pH and reduction of eubiotic microbiota. Herein, we evaluated the effects of the potent trichomonacidal compound, copper(II)-1,10-phenanthroline-5,6-dione (Cu-phendione), against pathogens responsible for candidiasis and aerobic vaginitis. Cu-phendione showed antimicrobial activity against Candida albicans, non-albicans Candida species (C. glabrata, C. krusei, C. parapsilosis, and C. tropicalis) and Gram-negative (Escherichia coli) and Gram-positive (Staphylococcus aureus, Enterococcus faecalis, and Streptococcus agalactiae) bacteria. Moreover, Cu-phendione was able to interfere with the fungal biofilm formation. These results highlight the antimicrobial potential of Cu-phendione against bacterial and fungal strains of vaginitis-causing infectious agents.

Developing Novel Coumarin-Containing Azoles Antifungal Agents by the Scaffold Merging Strategy for Treating Azole-Resistant Candidiasis.

The extensive use of antifungal drugs has resulted in severe drug resistance, making clinical treatment of fungal infections more difficult. Biofilm inhibitors can overcome drug resistance by inhibiting fungal biofilm formation. In this study, some coumarins with antibiofilm activity were merged into CYP51 inhibitors to produce novel molecules possessing potent antiresistance activity. As expected, most compounds exhibited excellent in vitro antifungal activity against pathogenic fungi, especially fluconazole-resistant candidiasis. Then, their mechanism was confirmed by sterol composition analysis and morphological observation. Biofilm inhibition and down-regulation of resistance-related genes were employed to confirm the compounds' antiresistance mechanisms. Significantly, compound A32 demonstrated fungicidal activity against fluconazole-resistant strain 904. Most importantly, compound A32 showed potent in vivo antifungal activity against pathogenic fungi and fluconazole-resistant strains. Preliminary pharmacokinetic and toxicity tests demonstrated that the compounds possessed favorable druggability. Taken together, compound A32 represents a promising lead to develop novel antifungal agents for treating azole-resistant candidiasis.