Search Results (510)

Metabolomics has emerged as a transformative tool in the study of microbes, including pathogenic fungi, facilitating the identification of unique metabolic profiles that elucidate their pathogenic mechanisms, host interactions, and treatment resistance. This review highlights key applications of metabolomics in understanding fungal metabolites essential for human virulence, such as mycotoxins produced by various fungal species, including Aspergillus fumigatus (gliotoxin, fumagillins) and Candida species (phenylethyl alcohol, TCA cycle metabolites), and secondary metabolites that contribute to pathogenicity. It also explores the metabolic adaptations of fungi in relation to drug resistance and biofilm formation, revealing alterations in key metabolic pathways during infection, as seen in C. albicans and C. auris. Furthermore, metabolomics aids in deciphering host–pathogen interactions, showcasing how fungi like Cryptococcus neoformans and Candida modify host metabolism to promote survival and evade immune responses. The study of antifungal resistance mechanisms has also benefited from metabolomic approaches, identifying specific metabolite patterns that signify resistance, such as in Candida albicans and Candidozyma (Candida) auris, and informing new therapeutic strategies. The integration of metabolomics with other omics technologies is paving the way for a comprehensive understanding of fungal biology and pathogenesis. Such multi-omics approaches are crucial for discovering new therapeutic targets and developing innovative antifungal treatments. Thus, the purpose of this review is to provide an overview of how metabolomics is revolutionizing our understanding of fungal pathogenesis, drug resistance, and host interactions, and to highlight its potential for identifying new therapeutic targets and improving antifungal strategies. Full article

Soil salinity, affecting 20–50% of irrigated farmland globally, poses a significant threat to agriculture and food security, worsened by climate change and increasing droughts. Traditional methods for managing saline soils—such as leaching, gypsum addition, and soil excavation—are costly and often unsustainable. An alternative approach using plant growth-promoting microorganisms (PGPMs) offers promise for improving crop productivity in saline conditions. This study tested twenty-three bacterial strains, one yeast, and one fungal strain, isolated from diverse sources including salicornia plants, sandy soils, tomato stems or seeds, tree leaves, stems, and flowers. They were initially submitted to in vitro selection tests to assess their ability to promote plant growth under salt stress. In vitro tests included auxin production, phosphate solubilization, and co-culture of microorganisms and tomato seedlings in salt-supplemented media. The Bacillus sp. strain 44 showed the highest auxin production, while Bacillus megaterium MJ had the strongest phosphate solubilization ability. Cryptococcus sp. STSD 4 and Gliomastix murorum (4)10-1(iso1) promoted germination and the growth of tomato seedlings in an in vitro co-culture test performed on a salt-enriched medium. This innovative test proved particularly effective in selecting relevant strains for in planta trials. The microorganisms that performed best in the various in vitro tests were then evaluated in vivo on tomato plants grown in greenhouses. The results showed significant improvements in growth, including increases in fresh and dry biomass and stem size. Among the strains tested, Gliomastix murorum (4)10-1(iso1) stood out, delivering an increase in fresh biomass of 94% in comparison to the negative control of the salt modality. These findings highlight the potential of specific PGPM strains to enhance crop resilience and productivity in saline soils, supporting sustainable agricultural practices. Full article

Background: Despite kidney transplantation being a life-saving procedure, patients experience a high risk of developing fungal infections (FIs), with an increased risk of both morbidity and mortality, especially during the first year after transplant. Methods: We herein conducted a narrative review of the most common FIs in kidney transplant recipients (KTRs), with a focus on prevalence, risk factors, mortality, and prevention strategies. Results: The most common fungal pathogens in KTRs include Candida species (up to 70% of the overall FIs), Aspergillus species, Pneumocystis jiroveci, and Cryptococcus species. Fungal colonization, diabetes mellitus, chronic liver disease, malnutrition, and pre-existing lung conditions should all be acknowledged as possible predisposing risk factors. The mortality rate can vary from 25 to 50% and according to different settings and the types of FIs. Preventive strategies are critical for reducing the incidence of FIs in this population. These include antifungal prophylaxis, environmental precautions, and infection control measures. The use of novel tools (such as PCR-based molecular assays and NGS) for rapid and accurate diagnosis may play an important role. Conclusions: Early recognition, the appropriate use of antifungal therapy, and preventive strategies are essential for improving graft loss and fatal outcomes in this vulnerable population. Future research is needed to optimize diagnostic tools, identify novel antifungal agents, and develop better prophylactic strategies for high-risk transplant recipients. Full article

Fungal infections have become a growing concern in healthcare, particularly in immunocompromised individuals, with species like Candida, Cryptococcus, and Sporothrix posing significant challenges due to rising resistance and limited treatment options. In response, novel antifungal agents are being explored, including thiazolyl hydrazones. This study focuses on the development of a novel thiazolylhydrazone derivative, RW3. RW3 was synthesized to improve its water solubility and pharmacokinetic properties. The compound demonstrated a broad antifungal spectrum, particularly effective against Cryptococcus neoformans and Candida auris, with minimal irritant potential and low cytotoxicity. RW3 showed favorable solubility and high intestinal permeability, indicating potential for oral administration. The results suggest RW3 as a promising lead for further development as a therapeutic agent for systemic fungal infections. These findings underscore the importance of optimizing drug properties to enhance efficacy and safety profiles, opening the path for the development of innovative antifungal treatments. Full article

Cryptococcosis is a fungal disease in humans and animals, caused by the Cryptococcus neoformans and Cryptococcus gattii species complexes. Clinical cryptococcosis primarily manifests as upper respiratory tract disease; however, dissemination to other organs, particularly the brain, can occur. Nasal colonisation and subclinical cryptococcosis are common in koalas (Phascolarctos cinereus) due to their shared environmental niche with Cryptococcus: Eucalyptus trees. However, for reasons that remain unclear, the prevalence of clinical disease is low in koalas. Interactions between respiratory pathogens and the nasal mycobiome are thought to play a role in the development and progression of numerous respiratory diseases. As such, this study aimed to characterise the mycobiome of the nasal vestibule in koalas with and without evidence of cryptococcal colonisation and subclinical disease via the next-generation sequencing (NGS) of the ITS1 region of the fungal internal transcribed spacer (ITS) gene. Samples were collected from 47 koalas from a population of free-ranging koalas in the Liverpool Plains, NSW, Australia, with a known history of Cryptococcus exposure and nasal colonisation. Of the 47 animals tested, 6.4% were culture-positive only, 4.3% were seropositive only, and 2.1% were culture- and seropositive. C. gattii was detected in four samples via NGS. C. neoformans was not detected via NGS. There were no significant differences in the nasal mycobiomes of Cryptococcus-positive and -negative animals; thus, we could not establish a definitive association between the mycobiome and infection outcomes. We identified a number of fungal genera that were significantly more abundant in samples from Cryptococcus-positive animals, but there was no apparent relationship between these genera and the development of cryptococcosis. This study represents the first investigation of the nasal mycobiota of wild koalas. Further studies involving koalas with clinical disease are necessary to determine the role of the nasal mycobiota in the development of cryptococcosis. Full article

Introduction: Cryptococcal meningitis is a major cause of death in HIV/AIDS patients due to the existence of Cryptococcus neoformans in the central nervous system. Our objective was to evaluate the prevalence of Cryptococcus antigenuria in a population of HIV-infected patients in Libreville, Gabon. Patients and Methods: This study was conducted from April to October 2021 at the Infectious Diseases ward of the Centre Hospitalier Universitaire de Libreville. Hospitalized patients with HIV were included. The detection of cryptococcal antigen (CrAg) in urine was performed using the Pastorex Crypto Plus Kit. Results: Out of the 255 PLHIV, 142 benefited from the CrAg detection. The prevalence of urine CrAg was 24.6% (n = 35). The majority of CrAg+ patients (82.8%; n = 29) were under 55 years old. Almost three-quarters of them (n = 25; 71.4%) had CD4 counts < 200, and 80.0% (n = 28) were at WHO clinical stages III and IV. All patients with neck stiffness at admission had a CrAg positive test. Conclusion: This study showed a non-negligible prevalence of Cryptococcal urinary antigen in HIV-infected patients with neurological symptoms. These data underline the importance of CrAg screening in routine care for better management of PLHIV. Full article

Cryptococcus neoformans is a globally distributed human fungal pathogen that can cause cryptococcal meningitis with high morbidity and mortality. In this study, we identified an anaphase-promoting complex (APC) activator, Cdh1, and examined its impact on the virulence of C. neoformans. Our subcellular localization analysis revealed that Cdh1 is situated in the nucleus of C. neoformans. Disrupting or overexpressing the CDH1 gene caused abnormal capsule formation in C. neoformans. The cdh1Δ mutant displayed slight sensitivity when grown at 37 °C, indicating that Cdh1 plays a role in maintaining the growth of C. neoformans at 37 °C. A fungal virulence assay showed that Cdh1 is closely associated with the virulence of C. neoformans, and both the cdh1Δ mutant and CDH1^OE overexpression strains significantly diminished the virulence of C. neoformans. The Cryptococcus–macrophage interaction assay revealed that both the cdh1∆ mutant and the CDH1^OE strains had significantly lower proliferation ability inside macrophages. Furthermore, the infection of the cdh1Δ mutant significantly activated neutrophil recruitment, as well as Th2 and Th17 immune responses, in lung tissue. In summary, our findings indicate that Cdh1 is crucial for producing virulence factors and fungal virulence in C. neoformans. The findings of this study can offer valuable insights and form the basis for further study of the regulatory mechanisms governing the pathogenicity of C. neoformans, potentially leading to the development of novel therapeutic strategies. Full article

Green propolis, particularly from the unique flora of the Brazilian Caatinga biome, has gained significant interest due to its diverse chemical composition and biological activities. This study focuses on the chemical characterization and antimicrobial evaluation of Caatinga green propolis. Twelve compounds were isolated through different chromatographic techniques, including flavanones (naringenin, 7-O-methyleriodictyol, sakuranetin), flavones (hispidulin, cirsimaritin), flavonols (quercetin, quercetin-3-methyl ether, kaempferol, 6-methoxykaempferol, viscosine, penduletin), and one chalcone (kukulkanin B). Using liquid chromatography–quadrupole time-of-flight tandem mass spectrometry (LC-QToF-MS), a total of 55 compounds excluding reference standards were tentatively identified, which include flavonoids, phenolic acids derivatives, and alkaloids, with flavonols, flavanones, and flavones being predominant. Antimicrobial testing against pathogens revealed that the crude extract exhibited low inhibitory activity, against Gram-positive bacteria, including methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus faecium (VRE) (IC₅₀: 148.4 and 120.98 µg/mL, respectively). Although the isolated compounds showed limited individual activity, a fraction containing sakuranetin and penduletin (Fraction 8) exhibited moderated activity against Cryptococcus neoformans (IC₅₀: 47.86 µg/mL), while a fraction containing quercetin and hispidulin showed moderated activity against VRE (IC₅₀: 16.99 µg/mL). These findings highlight the potential application of Caatinga green propolis as an antimicrobial agent, particularly against resistant bacterial strains, and underscore the importance of synergistic interactions between compounds in enhancing biological effects. Full article

The venoms of Theraphosidae spiders have evolved into diverse natural pharmacopeias through selective pressures. Cryptococcus neoformans is a global health threat that frequently causes life-threatening meningitis and fungemia, particularly in immunocompromised patients. In this study, we identify a novel anti-C. neoformans peptide, QS18 (QCFKVCFRKRCFTKCSRS), from the venom gland of China’s native spider species Chilobrachys liboensis by utilizing bioinformatic tools. QS18 shares over 50% sequence similarity with tachyplesin peptides, previously identified only in horseshoe crab hemocytes, expanding the known repertoire of the tachyplesin family to terrestrial arachnids. The oxidative folding of QS18 notably enhances its antifungal activity and stability, resulting in a minimum inhibitory concentration of 1.4 µM. The antimicrobial mechanism of QS18 involves cell membrane disruption. QS18 exhibits less than 5% hemolysis in human erythrocytes, indicating microbial selectivity and a favorable safety profile for therapeutic use. Furthermore, mouse model studies highlight QS18’s ability as an antifungal agent with notable anti-inflammatory activity. Our study demonstrates QS18 as both a promising template for spider venom peptide research and a novel candidate for the development of peptide antifungals. Full article

Antimicrobial compounds play a critical role in combating microbial infections. However, the emergence of antibiotic and antifungal resistance and the scarcity of new antibiotic developments pose a significant threat and demand the discovery of new antimicrobials for both bacterial and fungal pathogens. Our previous work described the first generation (G1) of organoantimony-based compounds that showed antimicrobial activity against several bacterial and fungal pathogens. Here, we present our efforts in modifying these compounds by replacing the tetraphenyl backbone in G1 compounds with a trimethyl group, thereby generating a new series of compounds we refer to as “generation 2”, G2. In addition to the novel backbone structure, we introduced three new anionic chloro-cyanoxime ligand groups, namely 2,4-diCl-PhCO⁻, 2,6-diCl-PhCO⁻ and 2Cl-PhCO⁻, which were found to be biologically active in the past. Nine new compounds of SbMe₃L₂ composition were obtained in high yields and characterized by NMR, IR spectroscopies, thermogravimetric TG/DSC and X-ray single crystal analyses. The antibacterial activity of the cyanoximates was tested against three bacterial (Pseudomonas aeruginosa PAO1, Escherichia coli S17 and methicillin-resistant Staphylococcus aureus (MRSA) NRS70) and two fungal (Candida albicans strain SC5314 and Cryptococcus neoformans strain H99) pathogens. Two compounds, SbMe₃(MCO)₂ and SbMe₃(2,4-diClPhCO)₂, were active against bacterial strains and inhibited the growth of PAO1 and MRSA with MICs of 50 and 100 µg/mL, respectively. Three compounds, SbMe₃(MCO)₂, SbMe₃(ECO)₂ and SbMe₃(TCO)₂, were active against fungal strains and inhibited either one of or both C. albicans and C. neoformans at MICs of 2.6–66.67 μg/mL. In addition, SbMe₃(TCO)₂ and SbMe₃(MCO)₂ were fungicidal at MFC 33.33–66.67 μg/mL. Ultra-thin-layer TEM imaging suggested that SbMe₃(MCO)₂ targets the integrity of bacterial membranes. Overall, four of the studied G2 series compounds possess antimicrobial activity against a broad range of microbial pathogens, with particular potential against fungal pathogens, which will be explored in further studies. Full article

Cryptococcus neoformans is an opportunistic fungal pathogen that is a continuous global health concern, especially for immunocompromised populations. The World Health Organization recognized C. neoformans as one of four critical fungal pathogens, thus emphasizing the need for increased research efforts and clinical resource expansion. Currently, there are no fungal vaccines available for clinical use. Exciting new findings in cryptococcal vaccine development have identified whole cell-based and subunit-based vaccinations to help mitigate health risks and make commercialization attainable. Importantly, recent work has focused on how different cryptococcal cell-wall antigens modified in these vaccine candidates allow us to manipulate their immunogenicity to produce a desired long-term protective anti-fungal immune response. In this review, we discuss the different cryptococcal cell immunogens, namely the polysaccharide capsule, glucans, chitin/chitosan, mannoproteins, and extracellular vesicles, and their role in novel cryptococcal vaccination approaches. Additionally, we examine the immunological mechanisms responsible for protection in these vaccine candidates and the similar host response-stimulation pathways induced through different immunogen exposure. Full article

In this study, metagenomic analysis was employed to investigate the bacterial communities in the Muan tidal mudflat of the Republic of Korea. We used metagenomic analysis to identify the microbial community in tidal soil dominated by Proteobacteria. From this environment, the bacterial strain, Saccharomonospora sp. CMS18, was isolated and yielded two previously unknown compounds, penipaline D (3) and N-acetyl-dimethylallyltryptophan (4). The chemical structures of the isolated compounds along with 6-dimethylallyl-indole (1), 6-dimethylallyltryptophan (2), penipaline D (3), and N-acetyl-dimethylallyltryptophan (4) were structurally investigated using HR-ESI-MS and NMR spectroscopy. The isolated compound 6-dimethylallyl-indole (1) demonstrated broad-spectrum antifungal activity, with IC₅₀ value of 0.04 mM against Candida glabrata and 0.35 mM against both Candida albicans and Cryptococcus neoformans. Additionally, it exhibited additive interaction with caspofungin against C. albicans. Full article

This study investigates the effect of maceration and different winemaking techniques on the species diversity of yeasts in white wines from the Slovak Tokay wine region, known for its traditional white wine production. Lipovina grape variety samples were divided into three groups: control (C), macerated (M) and macerated with the addition of a yeast culture (MY). During the entire fermentation process, quantitative and qualitative microbiological analyses of the raw material and must samples were carried out, which resulted in the identification of 60 yeast isolates via the API 20 C AUX biochemical test and MALDI-TOF MS. Identification was further verified via Sanger sequencing of PCR amplicons, which confirmed the presence of less common wild yeasts in Tokay wine must samples, including Aureobasidium pullulans, Cryptococcus magnus, Torulaspora delbrueckii and Rhodotorula sp. The highest species diversity was observed in the macerated group. These findings indicate that the quality and distinctiveness of Slovak Tokay wines can be increased by careful management of the maceration process during winemaking procedures. Full article

Cryptococcal infection commonly begins as an opportunistic infection in humans, however, this can escalate to a systemic or life-threatening form in immunocompromised individuals. Here, we aim to identify novel antifungal molecules from plants resources. Sclareolide, a phytochemical classified as a sesquiterpene lactone, was assessed against Cryptococcus neoformans H99. Sclareolide exhibited promising antifungal properties with a minimum inhibitory concentration (MIC) of 16 µg/mL. Additionally, the C. neoformans growth rate was significantly affected by sclareolide treatment in a concentration-dependent manner, as observed through a time killing assay, with a significant reduction at MIC × 8 compared to the control by 48 h. To elucidate the underlying mechanisms of sclareolide antifungal activity, fluorescence-based methods were employed. Propidium iodide (PI) accumulation assay indicated a reduction in C. neoformans membrane integrity, with values as low as 6.62 ± 0.18% after treatment. Moreover, sclareolide at MIC × 4 and MIC × 8 significantly increased the production of reactive oxygen species (ROS) and reduced the mitochondrial membrane potential (MMP), suggesting oxidative stress and mitochondrial dysfunction in C. neoformans. Sclareolide did not induce caspase-dependent apoptosis, suggesting a non-apoptotic mechanism. Further, a checkerboard experiment was performed to assess potential synergistic interaction with Amphotericin B, however, no synergism was observed. Moving on, sclareolide at 128 µg/mL did not exhibit toxicity in Galleria mellonella, further supporting its potential as a safe antifungal agent. These findings suggest that the antifungal activity of sclareolide against C. neoformans is mediated by oxidative stress. Further in vivo and pharmacokinetic studies are recommended to explore the potential of sclareolide as a prototype for the development of novel anti-cryptococcal therapies. Full article

Cryptococcus neoformans is a widespread fungal pathogen that can infect the human central nervous system (CNS) and cause fungal meningitis, leading to hundreds of thousands of deaths worldwide each year. Previous studies have demonstrated that many signal transduction pathways are crucial for the morphological development and virulence of C. neoformans. In this review, data from over 116 research articles have been compiled to show that many signaling pathways control various characteristics of C. neoformans, individually or in association with other pathways, and to establish strong links among them to better understand C. neoformans pathogenesis. Every characteristic of C. neoformans is closely linked to these signaling pathways, making this a rich area for further research. It is essential to thoroughly explore these pathways to address questions that remain and apply a molecular mechanistic approach to link them. Targeting these pathways is crucial for understanding the exact mechanism of infection pathogenesis and will facilitate the development of antifungal drugs as well as the diagnosis and prevention of cryptococcosis. Full article