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International Journal of Antimicrobial... Jun 2015Natamycin is a poorly soluble, polyene macrolide antifungal agent used in the food industry for the surface treatment of cheese and sausages. This use is not of safety... (Review)
Review
Natamycin is a poorly soluble, polyene macrolide antifungal agent used in the food industry for the surface treatment of cheese and sausages. This use is not of safety concern. However, highly soluble natamycin-cyclodextrin inclusion complexes have been developed for the protection of beverages. This practice leads to high drug exposures exceeding the safety level. Apart from the definition of an acceptable daily dietary exposure to natamycin, its effect on the faecal flora as a reservoir for resistance has to be examined. Consumption of food to which natamycin has been added and mixed homogeneously, such as yoghurt, and in particular the addition of cyclodextrin inclusion complexes to beverages and wine generates high faecal natamycin concentrations resulting in high drug exposures of faecal Candida spp. Development of natamycin resistance has been observed in Candida spp. colonising the intestinal tract of patients following natamycin treatment of fungal infections. Horizontal gene transfer among different Candida spp. and within Aspergillus fumigatus spreads resistance. Therefore, it cannot be denied that use of natamycin for preservation of yoghurt and beverages may foster development of resistance to polyenes in Candida spp.
Topics: Amphotericin B; Antifungal Agents; Aspergillus fumigatus; Candida; Drug Resistance, Fungal; Food Preservation; Food Preservatives; Gene Transfer, Horizontal; Humans; Natamycin; Selection, Genetic; Treatment Outcome
PubMed: 25862309
DOI: 10.1016/j.ijantimicag.2015.02.011 -
Cell Death & Disease May 2021Ciclopirox (CPX) is an FDA-approved topical antifungal agent that has demonstrated preclinical anticancer activity in a number of solid and hematologic malignancies. Its...
Ciclopirox (CPX) is an FDA-approved topical antifungal agent that has demonstrated preclinical anticancer activity in a number of solid and hematologic malignancies. Its clinical utility as an oral anticancer agent, however, is limited by poor oral bioavailability and gastrointestinal toxicity. Fosciclopirox, the phosphoryloxymethyl ester of CPX (Ciclopirox Prodrug, CPX-POM), selectively delivers the active metabolite, CPX, to the entire urinary tract following parenteral administration. We characterized the activity of CPX-POM and its major metabolites in in vitro and in vivo preclinical models of high-grade urothelial cancer. CPX inhibited cell proliferation, clonogenicity and spheroid formation, and increased cell cycle arrest at S and G0/G1 phases. Mechanistically, CPX suppressed activation of Notch signaling. Molecular modeling and cellular thermal shift assays demonstrated CPX binding to γ-secretase complex proteins Presenilin 1 and Nicastrin, which are essential for Notch activation. To establish in vivo preclinical proof of principle, we tested fosciclopirox in the validated N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN) mouse bladder cancer model. Once-daily intraperitoneal administration of CPX-POM for four weeks at doses of 235 mg/kg and 470 mg/kg significantly decreased bladder weight, a surrogate for tumor volume, and resulted in a migration to lower stage tumors in CPX-POM treated animals. This was coupled with a reduction in the proliferation index. Additionally, there was a reduction in Presenilin 1 and Hes-1 expression in the bladder tissues of CPX-POM treated animals. Following the completion of the first-in-human Phase 1 trial (NCT03348514), the pharmacologic activity of fosciclopirox is currently being characterized in a Phase 1 expansion cohort study of muscle-invasive bladder cancer patients scheduled for cystectomy (NCT04608045) as well as a Phase 2 trial of newly diagnosed and recurrent urothelial cancer patients scheduled for transurethral resection of bladder tumors (NCT04525131).
Topics: Amyloid Precursor Protein Secretases; Antifungal Agents; Carcinoma, Transitional Cell; Ciclopirox; Humans; Neoplasm Grading
PubMed: 34059639
DOI: 10.1038/s41419-021-03836-z -
Frontiers in Cellular and Infection... 2023Antifungal agents are not always efficient in resolving vulvovaginal candidiasis (VVC), a common genital infection caused by the overgrowth of spp., including , or in...
INTRODUCTION
Antifungal agents are not always efficient in resolving vulvovaginal candidiasis (VVC), a common genital infection caused by the overgrowth of spp., including , or in preventing recurrent infections. Although lactobacilli (which are dominant microorganisms constituting healthy human vaginal microbiota) are important barriers against VVC, the metabolite concentration needed to suppress VVC is unknown.
METHODS
We quantitatively evaluated metabolite concentrations to determine their effect on spp., including 27 vaginal strains of , and , with inhibitory abilities against biofilms of clinical isolates.
RESULTS
culture supernatants suppressed viable fungi by approximately 24%-92% relative to preformed biofilms; however, their suppression differed among strains and not species. A moderate negative correlation was found between lactate production and biofilm formation, but no correlation was observed between hydrogen peroxide production and biofilm formation. Both lactate and hydrogen peroxide were required to suppress planktonic cell growth. strains that significantly inhibited biofilm formation in culture supernatant also inhibited adhesion to epithelial cells in an actual live bacterial adhesion competition test.
DISCUSSION
Healthy human microflora and their metabolites may play important roles in the development of new antifungal agent against -induced VVC.
Topics: Female; Humans; Candida albicans; Hydrogen Peroxide; Lactobacillus; Candida; Candidiasis, Vulvovaginal; Antifungal Agents; Epithelial Cells; Biofilms
PubMed: 37201113
DOI: 10.3389/fcimb.2023.1113401 -
The ISME Journal Jun 2021Bacteria and fungi secrete many natural products that inhibit each other's growth and development. The dynamic changes in secreted metabolites that occur during...
Bacteria and fungi secrete many natural products that inhibit each other's growth and development. The dynamic changes in secreted metabolites that occur during interactions between bacteria and fungi are complicated. Pyochelin is a siderophore produced by many Pseudomonas and Burkholderia species that induces systemic resistance in plants and has been identified as an antifungal agent. Through imaging mass spectrometry and metabolomics analysis, we found that Phellinus noxius, a plant pathogen, can modify pyochelin and ent-pyochelin to an esterification product, resulting in reduced iron-chelation and loss of antifungal activity. We also observed that dehydroergosterol peroxide, the fungal metabolite, is only accumulated in the presence of pyochelin produced through bacteria-fungi interactions. For the first time, we show the fungal transformation of pyochelin in the microbial interaction. Our findings highlight the importance of understanding the dynamic changes of metabolites in microbial interactions and their influences on microbial communities.
Topics: Antifungal Agents; Fungi; Iron; Pseudomonas; Pseudomonas aeruginosa; Siderophores
PubMed: 33619352
DOI: 10.1038/s41396-020-00871-0 -
Antimicrobial Agents and Chemotherapy Jan 1997T-8581 is a new water-soluble triazole antifungal agent. The geometric mean IC80s (GM-IC80S; where the IC80 is the lowest drug concentration which reduced the optical... (Comparative Study)
Comparative Study
T-8581 is a new water-soluble triazole antifungal agent. The geometric mean IC80s (GM-IC80S; where the IC80 is the lowest drug concentration which reduced the optical density at 630 nm by 80% compared with the optical density at 630 nm of the drug-free control) for Candida albicans were as follows: T-8581, 0.218 microgram/ml; fluconazole; 0.148 microgram/ml; and itraconazole, 0.0170 microgram/ml. For Cryptococcus neoformans the GM-IC80s were as follows: T-8581, 9.28 micrograms/ml; fluconazole, 4.00 micrograms/ml; and itraconazole, 0.119 microgram/ml. For Aspergillus fumigatus the GM-IC80s were as follows: T-8581, 71.0 micrograms/ml; fluconazole, 239 micrograms/ml; and itraconazole, 0.379 microgram/ml. Against systemic candidiasis in mice, the 50% effective doses (ED50s) of T-8581, fluconazole, and itraconazole (given orally) were 0.412, 0.392, and > 320 mg/kg of body weight, respectively. Against systemic aspergillosis in mice, the ED50s of T-8581, fluconazole, and itraconazole (given orally) were 50.5, 138, > 320 mg/kg, respectively. T-8581 was also efficacious when it was given parenterally (ED50, 59.2 mg/kg), while the ED50 of fluconazole given parenterally was > 20 mg/kg. Against systemic aspergillosis in rabbits, T-8581 was more effective than fluconazole and itraconazole in prolonging the life span. The high concentrations of T-8581 were observed in the sera of mice, rats, rabbits and dogs. Species differences in half-lives and areas under the concentration-time curves were observed, with the values for mice, rats, rabbits, and dogs increasing in that order. These results suggest that T-8581 would be a potentially effective antifungal drug for oral and parenteral use.
Topics: Animals; Antifungal Agents; Aspergillosis; Aspergillus fumigatus; Candida; Candidiasis; Cryptococcus neoformans; Dogs; Fluconazole; Hydroxybutyrates; Itraconazole; Male; Mice; Mice, Inbred ICR; Microbial Sensitivity Tests; Rabbits; Rats; Triazoles
PubMed: 8980750
DOI: 10.1128/AAC.41.1.30 -
Chembiochem : a European Journal of... Dec 2021Sphaeropsidin A (SphA) is a tetracyclic pimarane diterpene, first isolated as the main phytotoxin produced by Diplodia cupressi the causal agent of a severe canker... (Review)
Review
Sphaeropsidin A (SphA) is a tetracyclic pimarane diterpene, first isolated as the main phytotoxin produced by Diplodia cupressi the causal agent of a severe canker disease of Italian cypress (Cupressus sempervirens L.). It was also produced, together with several analogues, by different pathogenic Diplodia species and other fungi and showed a broad array of biological activities suggesting its promising application in agriculture and medicine. The anticancer activity of SphA is very potent and cell specific. Recent studies have revealed its unique mode of action. This minireview reports the structures of SphA and its family of natural analogues, their biosynthetic origins, their fungal sources, and biological activities. The preparation of various SphA derivatives is also described as well as the results of structure-activity relationship (SAR) studies and on their potential practical applications.
Topics: Antifungal Agents; Antineoplastic Agents; Ascomycota; Diterpenes; Microbial Sensitivity Tests; Molecular Structure; Structure-Activity Relationship
PubMed: 34241944
DOI: 10.1002/cbic.202100283 -
Journal of Medicinal Chemistry Dec 2015Cationic amphiphiles derived from aminoglycosides (AGs) have been shown to exhibit enhanced antimicrobial activity. Through the attachment of hydrophobic residues such...
Cationic amphiphiles derived from aminoglycosides (AGs) have been shown to exhibit enhanced antimicrobial activity. Through the attachment of hydrophobic residues such as linear alkyl chains on the AG backbone, interesting antibacterial and antifungal agents with a novel mechanism of action have been developed. Herein, we report the design and synthesis of seven kanamycin B (KANB) derivatives. Their antibacterial and antifungal activities, along with resistance/enzymatic, hemolytic, and cytotoxicity assays were also studied. Two of these compounds, with a C12 and C14 aliphatic chain attached at the 6″-position of KANB through a thioether linkage, exhibited good antibacterial and antifungal activity, were poorer substrates than KANB for several AG-modifying enzymes, and could delay the development of resistance in bacteria and fungi. Also, they were both relatively less hemolytic than the known membrane targeting antibiotic gramicidin and the known antifungal agent amphotericin B and were not toxic at their antifungal MIC values. Their oxidation to sulfones was also demonstrated to have no effect on their activities. Moreover, they both acted synergistically with posaconazole, an azole currently used in the treatment of human fungal infections.
Topics: Animals; Anti-Bacterial Agents; Antifungal Agents; Bacteria; Bacterial Infections; Cell Line; Cell Survival; Drug Design; Drug Resistance, Microbial; Fungi; Hemolysis; Humans; Kanamycin; Mice; Mycoses; Surface-Active Agents
PubMed: 26592740
DOI: 10.1021/acs.jmedchem.5b01375 -
Molecules (Basel, Switzerland) May 2020Gentamicin is a broad-spectrum aminoglycoside antibiotic produced by bacteria, effective against Gram-negative bacterial infections. Major fractions of the gentamicin...
BACKGROUND
Gentamicin is a broad-spectrum aminoglycoside antibiotic produced by bacteria, effective against Gram-negative bacterial infections. Major fractions of the gentamicin complex (C1, C1a, C2, C2a) possess weak antifungal activity and one of the minor components (A, A1-A4, B, B1, X), gentamicin B1 was found to be a strong antifungal agent.
METHODS
This work uses in vitro and in vivo dilution methods to compare the antifusarial, antiaspergillic and anticryptococcal effects of gentamicin derivatives and structurally-related congeners.
RESULTS
The in vitro antifusarial activity of gentamicin B1 (minimum inhibitory concentration (MIC) 0.4 μg/mL) and structurally-related compounds (MIC 0.8-12.5 μg/mL) suggests that the purpuroseamine ring substituents are responsible for the specific antimycotic effect. The functional groups of the garoseamine and 2-deoxystreptamine rings of gentamicin derivatives are identical in gentamicin compounds and are unlikely to exert a significant antifungal effect. Among soil dermatophytes, was more susceptible to gentamicin B1 (MIC 3.1 µg/mL) than (MIC 25 µg/mL). The in vitro antifungal effect of gentamicin B1 against plant pathogenic fungi was comparable to primary antifungal agents.
CONCLUSION
Gentamicin is already in medical use. In vitro and preclinical in vivo synergisms of gentamicin B1 with amphotericin B suggest immediate clinical trials starting with subtoxic doses.
Topics: Antifungal Agents; Arthrodermataceae; Fungi; Gentamicins; Humans; Microbial Sensitivity Tests; Mycoses; Plant Diseases
PubMed: 32455775
DOI: 10.3390/molecules25102401 -
Antimicrobial Agents and Chemotherapy Oct 2021Rezafungin is a novel antifungal agent of the echinocandin class with potent activity against species of and Aspergillus, including subsets of resistant strains, and...
Rezafungin is a novel antifungal agent of the echinocandin class with potent activity against species of and Aspergillus, including subsets of resistant strains, and Pneumocystis jirovecii. The objective of this analysis was to develop a population pharmacokinetic (PK) model to characterize the disposition of rezafungin in plasma following intravenous (IV) administration in healthy volunteers and in patients with candidemia and/or invasive candidiasis. The population PK model was based on a previous model from phase 1 data; formal covariate analyses were conducted to identify any relationships between subject characteristics and rezafungin PK variability. A four-compartment model with linear elimination and zero-order drug input provided a robust fit to the pooled data. Several statistically significant relationships between subject descriptors (sex, infection status, serum albumin, and body surface area [BSA]) and rezafungin PK parameters were identified, but none were deemed clinically relevant. Previous dose justification analyses conducted using data from phase 1 subjects alone are expected to remain appropriate. The final model provided a precise and unbiased fit to the observed concentrations and can be used to reliably predict rezafungin PK in infected patients.
Topics: Antifungal Agents; Candida; Candidiasis, Invasive; Echinocandins; Humans
PubMed: 34398673
DOI: 10.1128/AAC.00842-21 -
Scientific Reports Nov 2021Fungicides are extensively used in agriculture to control fungal pathogens which are responsible for significant economic impact on plant yield and quality. The...
Fungicides are extensively used in agriculture to control fungal pathogens which are responsible for significant economic impact on plant yield and quality. The conventional antifungal screening techniques, such as water agar and 96-well plates, are based on laborious protocols and bulk analysis, restricting the analysis at the single spore level and are time consuming. In this study, we present a droplet-based microfluidic platform that enables antifungal analysis of single spores of filamentous fungus Alternaria alternata. A droplet-based viability assay was developed, allowing the germination and hyphal growth of single A. alternata spores within droplets. The viability was demonstrated over a period of 24 h and the antifungal screening was achieved using Kunshi/Tezuma as antifungal agent. The efficacy results of the droplet-based antifungal analysis were compared and validated with the results obtained from conventional protocols. The percentage inhibitions assessed by the droplet-based platform were equivalent with those obtained by the other two methods, and the Pearson correlation analysis showed high correlation between the three assays. Taken together, this droplet-based microfluidic platform provides a wide range of potential applications for the analysis of fungicide resistance development as well as combinatorial screening of other antimicrobial agents and even antagonistic fungi.
Topics: Alternaria; Antifungal Agents; Biological Assay; High-Throughput Screening Assays; Microfluidics
PubMed: 34836995
DOI: 10.1038/s41598-021-02350-8