Only three classes of antifungal drugs are currently in clinical use. Here, we report that derivatives of the malarial drug mefloquine have broad-spectrum antifungal activity including difficult-to-treat molds and endemic fungi. Pharmacokinetic and efficacy studies of NSC-4377 indicate that it penetrates the central nervous system and is active against .
View Article and Find Full Text PDFOnly three classes of antifungal drugs are currently in clinical use. Here, we report that derivatives of the malarial drug mefloquine have broad spectrum antifungal activity including difficult to treat molds and endemic fungi. Pharmacokinetic and efficacy studies of NSC-4377 indicate it penetrates the central nervous system and is active against in vivo.
View Article and Find Full Text PDFAntimicrob Agents Chemother
August 2024
Biofilm formation by the fungal pathogen Candida albicans is the basis for its ability to infect medical devices. The metabolic gene ERG251 has been identified as a target of biofilm transcriptional regulator Efg1, and here we report that ERG251 is required for biofilm formation but not conventional free-living planktonic growth. An erg251Δ/Δ mutation impairs biofilm formation in vitro and in an in vivo catheter infection model.
View Article and Find Full Text PDFThe epidemiology of invasive aspergillosis (IA) is evolving. To define the patient groups who will most likely benefit from primary or secondary prophylaxis, particularly those whose medical conditions and IA risk change over time, it is helpful to depict patient populations and their risk periods in a temporal visual model. The Sankey approach provides a dynamic figure to understand the risk of IA for various patient populations.
View Article and Find Full Text PDFThe opportunistic fungal pathogen Candida albicans damages host cells via its peptide toxin, candidalysin. Before secretion, candidalysin is embedded in a precursor protein, Ece1, which consists of a signal peptide, the precursor of candidalysin and seven non-candidalysin Ece1 peptides (NCEPs), and is found to be conserved in clinical isolates. Here we show that the Ece1 polyprotein does not resemble the usual precursor structure of peptide toxins.
View Article and Find Full Text PDFSF001 is a next-generation polyene antifungal drug in development, designed to have increased specificity to fungal ergosterol, which is absent in humans, and decreased binding to cholesterol. SF001 demonstrates long-acting, potent, broad-spectrum fungicidal activity. The goal of the current study was to determine the pharmacodynamic index and target of SF001 in an immunocompromised mouse model of invasive pulmonary aspergillosis against six isolates.
View Article and Find Full Text PDFThe host type I interferon (IFN) pathway is a major signature of inflammation induced by the human fungal pathogen, Candida albicans. However, the molecular mechanism for activating this pathway in the host defence against C. albicans remains unknown.
View Article and Find Full Text PDFThe newly emerged pathogen, , presents a serious threat to public health worldwide. This multidrug-resistant yeast often colonizes and persists on the skin of patients, can easily spread from person to person, and can cause life-threatening systemic infections. New antifungal therapies are therefore urgently needed to limit and control both superficial and systemic infections.
View Article and Find Full Text PDFis a commensal fungus that colonizes the human oral cavity and gastrointestinal tract but also causes mucosal as well as invasive disease. The expression of virulence traits in clinical isolates is heterogeneous and the genetic basis of this heterogeneity is of high interest. The reference strain SC5314 is highly invasive and expresses robust filamentation and biofilm formation relative to many other clinical isolates.
View Article and Find Full Text PDFTriazole antifungals (i.e., fluconazole, itraconazole, voriconazole, posaconazole, and isavuconazole) are commonly used in clinical practice to prevent or treat invasive fungal infections.
View Article and Find Full Text PDFUnlabelled: is a diploid human fungal pathogen that displays significant genomic and phenotypic heterogeneity over a range of virulence traits and in the context of a variety of environmental niches. Here, we show that the effects of Rob1 on biofilm and filamentation virulence traits is dependent on both the specific environmental condition and the clinical strain of . The reference strain SC5314 is a heterozygote with two alleles that differ by a single nucleotide polymorphism at position 946 resulting in a serine or proline containing isoform.
View Article and Find Full Text PDFRising drug resistance among pathogenic fungi, paired with a limited antifungal arsenal, poses an increasing threat to human health. To identify antifungal compounds, we screened the RIKEN natural product depository against representative isolates of four major human fungal pathogens. This screen identified NPD6433, a triazenyl indole with broad-spectrum activity against all screening strains, as well as the filamentous mold Aspergillus fumigatus.
View Article and Find Full Text PDFNew antifungal therapies are needed for both systemic, invasive infections in addition to superficial infections of mucosal and skin surfaces as well as biofilms associated with medical devices. The resistance of biofilm and biofilm-like growth phases of fungi contributes to the poor efficacy of systemic therapies to nonsystemic infections. Here, we describe the identification and characterization of a novel keto-alkyl-pyridinium scaffold with broad spectrum activity (2 to 16 μg/mL) against medically important yeasts and molds, including clinical isolates resistant to azoles and/or echinocandins.
View Article and Find Full Text PDFMethods Mol Biol
April 2023
Candida frequently produces three general disease states, including mucosal candidiasis, disseminated candidiasis, and biofilm infection (which can be present with either of the other disease states). Antifungal drug resistance is intrinsic to biofilm growth and has emerged in other disease states. Mechanistic studies have uncovered the genetic pathways governing resistance to a number of antifungal agents.
View Article and Find Full Text PDFAntimicrobial susceptibility testing (AST) remains the cornerstone of effective antimicrobial selection and optimization in patients. Despite recent advances in rapid pathogen identification and resistance marker detection with molecular diagnostics (, qPCR, MALDI-TOF MS), phenotypic (, microbial culture-based) AST methods - the gold standard in hospitals/clinics - remain relatively unchanged over the last few decades. Microfluidics-based phenotypic AST has been growing fast in recent years, aiming for rapid (, turnaround time <8 h), high-throughput, and automated species identification, resistance detection, and antibiotics screening.
View Article and Find Full Text PDFNew antifungal therapies are needed for both systemic, invasive infections as well as superficial infections of mucosal and skin surfaces as well as biofilms associated with medical devices. The resistance of biofilm and biofilm-like growth phases of fungi contributes to the poor efficacy of systemic therapies to non-systemic infections. Here, we describe the identification and characterization of a novel keto-alkyl-pyridinium scaffold with broad spectrum activity (2-16 µg/mL) against medically important yeasts and moulds, including clinical isolates resistant to azoles and/or echinocandins.
View Article and Find Full Text PDFBiofilms of the fungal pathogen Candida albicans include abundant long filaments called hyphae. These cells express hypha-associated genes, which specify diverse virulence functions including surface adhesins that ensure biofilm integrity. Biofilm formation, virulence, and hypha-associated gene expression all depend upon the transcription factor Efg1.
View Article and Find Full Text PDFFungal pathogens are a continuing challenge due to few effective antifungals and a rise in resistance. In previous work, we described the inhibition of Candida albicans virulence following exposure to the 68 amino acid bacteriocin, EntV, secreted by Enterococcus faecalis. Here, to optimize EntV as a potential therapeutic and better understand its antifungal features, an X-ray structure is obtained.
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