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Journal of Medicinal Chemistry Jun 2024The pathogenic fungus utilizes a cyclic ferrioxamine E (FOXE) siderophore to acquire iron from the host. Biomimetic FOXE analogues were labeled with gallium-68 for...
The pathogenic fungus utilizes a cyclic ferrioxamine E (FOXE) siderophore to acquire iron from the host. Biomimetic FOXE analogues were labeled with gallium-68 for molecular imaging with PET. [Ga]Ga(III)-FOXE analogues were internalized in cells via Sit1. Uptake of [Ga]Ga(III)-FOX 2-5, the most structurally alike analogue to FOXE, was high by both and bacterial . However, altering the ring size provoked species-specific uptake between these two microbes: ring size shortening by one methylene unit (FOX 2-4) increased uptake by compared to that by , whereas lengthening the ring (FOX 2-6 and 3-5) had the opposite effect. These results were consistent both and , including PET imaging in infection models. Overall, this study provided valuable structural insights into the specificity of siderophore uptake and, for the first time, opened up ways for selective targeting and imaging of microbial pathogens by siderophore derivatization.
PubMed: 38907990
DOI: 10.1021/acs.jmedchem.4c00887 -
Bioorganic & Medicinal Chemistry Jul 2024The antimicrobial activity of new acid-functionalized porphyrins, with or without ultra-high irradiance, was investigated. Antibacterial efficacy was evaluated against...
Synthesis and characterization of new acid-functionalized porphyrins displaying antimicrobial activity against gram positive bacteria, yeasts and filamentous fungi with or without ultra-high irradiance.
The antimicrobial activity of new acid-functionalized porphyrins, with or without ultra-high irradiance, was investigated. Antibacterial efficacy was evaluated against Staphylococcus aureus (methicillin-resistant or methicillin-sensitive strains) and antifungal efficacy was evaluated against the yeast Candida albicans and the filamentous fungi Aspergillus fumigatus. Overall, the porphyrins tested are more effective against S. aureus. The best results were obtained with zinc diacid porphyrins 4 and 5 after only 3 min of ultra-high irradiation (500 mW/cm, 405 nm), demonstrating that acid-functionalized porphyrins are promising as novel antimicrobial drugs for surface disinfection.
Topics: Microbial Sensitivity Tests; Porphyrins; Aspergillus fumigatus; Candida albicans; Antifungal Agents; Anti-Bacterial Agents; Gram-Positive Bacteria; Staphylococcus aureus; Structure-Activity Relationship; Molecular Structure; Dose-Response Relationship, Drug; Fungi
PubMed: 38906069
DOI: 10.1016/j.bmc.2024.117810 -
ACS Infectious Diseases Jun 2024Fungal keratitis (FK) is a severe corneal condition caused by pathogenic fungi and is associated with the virulence of fungi and an excessive tissue inflammatory...
Fungal keratitis (FK) is a severe corneal condition caused by pathogenic fungi and is associated with the virulence of fungi and an excessive tissue inflammatory response. Progranulin (PGRN), functioning as a multifunctional growth factor, exerts a pivotal influence on the regulation of inflammation and autophagy. The aim of our research was to analyze the role of PGRN in () keratitis. We found that PGRN expression was increased in the mouse cornea with keratitis. In our experiments, corneas of mice with FK were treated with 100 ng/mL of PGRN. In vitro, RAW 264.7 cells were treated with 10 ng/mL of PGRN before stimulation. The findings suggested that PGRN effectively alleviated corneal edema and decreased the expression of pro-inflammatory cytokines in mice. In stimulated RAW 264.7 cells, PGRN treatment suppressed the expression of pro-inflammatory cytokines IL-6 and TNF-α but promoted the expression of the anti-inflammatory cytokines IL-10. PGRN treatment significantly upregulated the expression of autophagy-related proteins LC3, Beclin-1, and Atg-7. 3-Methyladenine (3-MA, autophagy inhibitor) reversed the regulation of inflammatory cytokines by PGRN. In addition, our study demonstrated that PGRN also enhanced phagocytosis in RAW 264.7 cells. In summary, PGRN attenuated the inflammatory response of keratitis by increasing autophagy and enhanced the phagocytic activity of RAW 264.7 cells. This showed that PGRN had a protective effect on keratitis.
PubMed: 38900967
DOI: 10.1021/acsinfecdis.4c00236 -
Protein Science : a Publication of the... Jul 2024Tuberculosis necrotizing toxin (TNT) is a protein domain discovered on the outer membrane of Mycobacterium tuberculosis (Mtb), and the fungal pathogen Aspergillus...
Tuberculosis necrotizing toxin (TNT) is a protein domain discovered on the outer membrane of Mycobacterium tuberculosis (Mtb), and the fungal pathogen Aspergillus fumigatus. TNT domains have pure NAD(P) hydrolytic activity, setting them apart from other NAD-cleaving domains such as ADP-ribosyl cyclase and Toll/interleukin-1 receptor homology (TIR) domains which form a wider set of products. Importantly, the Mtb TNT domain has been shown to be involved in immune evasion via depletion of the intracellular NAD pool of macrophages. Therefore, an intriguing hypothesis is that TNT domains act as "NAD killers" in host cells facilitating pathogenesis. Here, we explore the phylogenetic distribution of TNT domains and detect their presence solely in bacteria and fungi. Within fungi, we discerned six TNT clades. In addition, X-ray crystallography and AlphaFold2 modeling unveiled clade-specific strategies to promote homodimer stabilization of the fungal enzymes, namely, Ca binding, disulfide bonds, or hydrogen bonds. We show that dimer stabilization is a requirement for NADase activity and that the group-specific strategies affect the active site conformation, thereby modulating enzyme activity. Together, these findings reveal the evolutionary lineage of fungal TNT enzymes, corroborating the hypothesis of them being pure extracellular NAD (eNAD) cleavers, with possible involvement in microbial warfare and host immune evasion.
Topics: Mycobacterium tuberculosis; NAD; Protein Domains; Fungal Proteins; Crystallography, X-Ray; Aspergillus fumigatus; Evolution, Molecular; Models, Molecular; Phylogeny; NAD+ Nucleosidase
PubMed: 38895984
DOI: 10.1002/pro.5071 -
PLoS Pathogens Jun 2024Invasive aspergillosis causes significant morbidity and mortality in immunocompromised patients. Natural killer (NK) cells are pivotal for antifungal defense. Thus far,...
Invasive aspergillosis causes significant morbidity and mortality in immunocompromised patients. Natural killer (NK) cells are pivotal for antifungal defense. Thus far, CD56 is the only known pathogen recognition receptor on NK cells triggering potent antifungal activity against Aspergillus fumigatus. However, the underlying cellular mechanisms and the fungal ligand of CD56 have remained unknown. Using purified cell wall components, biochemical treatments, and ger mutants with altered cell wall composition, we herein found that CD56 interacts with the A. fumigatus cell wall carbohydrate galactosaminogalactan (GAG). This interaction induced NK-cell activation, degranulation, and secretion of immune-enhancing chemokines and cytotoxic effectors. Supernatants from GAG-stimulated NK cells elicited antifungal activity and enhanced antifungal effector responses of polymorphonuclear cells. In conclusion, we identified A. fumigatus GAG as a ligand of CD56 on human primary NK cells, stimulating potent antifungal effector responses and activating other immune cells.
Topics: Humans; Aspergillus fumigatus; Killer Cells, Natural; CD56 Antigen; Aspergillosis; Lymphocyte Activation; Polysaccharides; Cell Wall
PubMed: 38889192
DOI: 10.1371/journal.ppat.1012315 -
The Clinical Respiratory Journal Jun 2024
Allergic Bronchopulmonary Aspergillosis (ABPA) With Colonized Aspergillus fumigatus Detected by Metagenomic Next-Generation Sequencing on Tissue Samples: A Distinct Subset of ABPA With a Higher Risk of Exacerbation.
Topics: Humans; Aspergillosis, Allergic Bronchopulmonary; Aspergillus fumigatus; Male; High-Throughput Nucleotide Sequencing; Female; Middle Aged; Metagenomics; Adult; Disease Progression; Aged
PubMed: 38886877
DOI: 10.1111/crj.13794 -
FEMS Microbiology Ecology Jun 2024Fungi are increasingly recognized to play diverse roles within honey bee hives, acting as pathogens, mutualists, and commensals. Pollen products, essential for hive...
Fungi are increasingly recognized to play diverse roles within honey bee hives, acting as pathogens, mutualists, and commensals. Pollen products, essential for hive nutrition, host significant fungal communities with potential protective and nutritional benefits. In this study, we profile the fungal communities and antifungal properties of three pollen products from healthy and stressed hives: fresh pollen collected by forager bees from local plants; stored pollen packed into the comb inside the hive; and bee bread, which is stored pollen following anaerobic fermentation used for bee and larval nutrition. Using amplicon sequencing, we found significant differences in fungal community composition, with hive health and sample type accounting for 8.8% and 19.3% of variation in beta diversity, respectively. Pollen and bee bread extracts had species-specific antimicrobial activity and inhibited the fungal hive pathogens Ascosphaera apis, Aspergillus flavus, and Aspergillus fumigatus, and the bacterial hive pathogen Paenibacillus larvae. Activity was positively correlated with phenolic and antioxidant content and was diminished in stressed hives. The plant source of pollen determined by amplicon sequencing differed in stressed hives, suggesting altered foraging behaviour. These findings illustrate the complex interplay between honey bees, fungal communities, and hive products, which should be considered in hive management and conservation.
Topics: Bees; Animals; Pollen; Fungi; Stress, Physiological; Paenibacillus larvae; Mycobiome; Ascomycota; Anti-Infective Agents
PubMed: 38886123
DOI: 10.1093/femsec/fiae091 -
Mycopathologia Jun 2024A 67 year-old male was admitted in the ICU because of multi-organ failure due to sepsis secondary to Fournier's gangrene. He had sustained radical prostatectomy in the...
A 67 year-old male was admitted in the ICU because of multi-organ failure due to sepsis secondary to Fournier's gangrene. He had sustained radical prostatectomy in the last 48 hours. Peritoneal fluid and fatty tissue biopsies grew Aspergillus Fumigatus without concomitant pulmonary involvement. Postoperative acquisition via exogenous and endogenous routes is discussed, as this nosocomial entity is very rarely reported apart from peritoneal dialysis, especially in non-immunosuppressed patients.
Topics: Humans; Male; Aspergillus fumigatus; Aged; Peritonitis; Aspergillosis; Postoperative Complications; Prostatectomy
PubMed: 38878212
DOI: 10.1007/s11046-024-00858-x -
Archives of Microbiology Jun 2024Aspergillus fumigatus is a ubiquitous filamentous fungus commonly found in the environment. It is also an opportunistic human pathogen known to cause a range of... (Review)
Review
Aspergillus fumigatus is a ubiquitous filamentous fungus commonly found in the environment. It is also an opportunistic human pathogen known to cause a range of respiratory infections, such as invasive aspergillosis, particularly in immunocompromised individuals. Azole antifungal agents are widely used for the treatment and prophylaxis of Aspergillus infections due to their efficacy and tolerability. However, the emergence of azole resistance in A. fumigatus has become a major concern in recent years due to their association with increased treatment failures and mortality rates. The development of azole resistance in A. fumigatus can occur through both acquired and intrinsic mechanisms. Acquired resistance typically arises from mutations in the target enzyme, lanosterol 14-α-demethylase (Cyp51A), reduces the affinity of azole antifungal agents for the enzyme, rendering them less effective, while intrinsic resistance refers to a natural resistance of certain A. fumigatus isolates to azole antifungals due to inherent genetic characteristics. The current review aims to provide a comprehensive overview of azole antifungal resistance in A. fumigatus, discusses underlying resistance mechanisms, including alterations in the target enzyme, Cyp51A, and the involvement of efflux pumps in drug efflux. Impact of azole fungicide uses in the environment and the spread of resistant strains is also explored.
Topics: Aspergillus fumigatus; Azoles; Drug Resistance, Fungal; Antifungal Agents; Humans; Fungal Proteins; Aspergillosis; Microbial Sensitivity Tests; Cytochrome P-450 Enzyme System; Mutation
PubMed: 38878211
DOI: 10.1007/s00203-024-04026-z -
The Pediatric Infectious Disease Journal Jun 2024Central nervous system (CNS) aspergillosis is an opportunistic infection with an increasing incidence and a high mortality rate. It is seen in immunocompromised patients...
INTRODUCTION
Central nervous system (CNS) aspergillosis is an opportunistic infection with an increasing incidence and a high mortality rate. It is seen in immunocompromised patients as well as in immunocompetent patients. Here, we present disseminated aspergillosis in a child with nephrotic syndrome treated with long-term and aggressive systemic antifungal treatment and intraventricular (IVent) liposomal amphotericin B (L-AmB) as well as surgical excision and drainage due to difficulty in management.
CASE REPORT
A 10-year-old boy with nephrotic syndrome on steroid therapy was admitted with limping and weakness. The cranial magnetic resonance imaging showed multiple intraparenchymal scattered abscesses. The largest one was excised and drained. Abscess culture revealed Aspergillus fumigatus and histopathological examination revealed septate hyphae compatible with Aspergillosis. Intravenous (IV) voriconazole was started, and IV L-AmB was added. The size of lesions and perilesional edema continued to increase, and then IVent L-AmB was added. With IVent and systemic antifungal treatment, regression of the lesions was observed. He was followed up with oral voriconazole and weekly IVent L-AmB. After 2 and a half months, he was re-operated because of increased lesion size, number and perilesional edema, and IV voriconazole and other salvage antifungal therapies were started. Since the lesions had decreased and remained stable, IV voriconazole was switched to oral therapy, and he was followed up as an outpatient. Immunodeficiency diseases were excluded by immunological and genetic tests.
CONCLUSION
Management of central nervous system aspergillosis can be challenging despite long-term and aggressive systemic and IVent antifungal treatment as well as surgical excision and drainage.
PubMed: 38865571
DOI: 10.1097/INF.0000000000004422