Project description:Exposure to endocrine-disrupting chemicals (EDCs) during fetal life is associated with reproductive disorders in humans. Although environmental EDCs have typically been the focus with respect to unintentional harm from developmental exposure, some medications, including commonly used antifungal agents, also exhibit endocrine-disrupting properties.
Project description:Fungal infections pose a growing global health challenge, exacerbated by a scarcity of effective treatments and rising drug resistance. Although cationic polymers emerge as promising antifungal candidates owing to structural tunability, design flexibility, and resistance to proteolytic degradation, their clinical utility has been hampered by non-selective membrane-disruption mechanisms. Herein, we develop a class of polycatechols- termed fungal iron predators (FIPs), exhibit exceptional fungicidal activity and markedly low cytotoxicity. These FIPs can efficiently infiltrate fungal cells, selectively sequester labile irons, and disrupt iron homeostasis and metabolism. The ensuing iron starvation provokes severe mitochondrial dysfunction and energy collapse, culminating in fungal cell death. Through systemic optimization of cationic density and catechol stoichiometry, we obtained an FIP variant demonstrating potent antifungal activity with high selectivity toward fungi over mammalian cells, minimal propensity to induce resistance, and supplementary antioxidant properties. Remarkably, this FIP candidate shows robust therapeutic performance across multiple in vivo models of fungal infection. Critically, this work established a groundbreaking paradigm in polymer design: shifting the antifungal mechanism from traditional non-specific membrane disruption to targeted intracellular metabolic interference. The general applicability of this strategy across diverse cationic polymer backbones opens avenues for developing next generation of precision antifungal agents.
Project description:Candida albicans is the leading cause of invasive candidiasis, causing life-threatening infections in immunocompromised individuals. Antifungal therapies are limited to three main drug classes, polyenes, azoles, and echinocandins, which target either the fungal membrane or fungal cell wall. Resistant isolates have been found for each of the three classes, and with the limited number of treatment options, there is an urgent need to develop new strategies against invasive fungal infections. Manogepix (MGX) is a novel antifungal currently undergoing phase 3 clinical trials, that functions by inhibiting glycosylphosphatidylinositol (GPI)-anchor biosynthesis. Nikkomycin Z (NikkZ) is a compound also being investigated for its antifungal properties that inhibits fungal chitin synthases. To date, the genes important for resistance to MGX and NikkZ are largely enigmatic. This project aims to identify and characterize C. albicans genes that modulate susceptibility to antifungals. To do so, we leveraged a large-scale collection of C. albicans Gene Replacement and Conditional Expression (GRACE) mutants with controllable gene expression through a doxycycline-repressible promoter. Specifically, we identified genes that modulate susceptibility to the echinocandin caspofungin, the azole fluconazole, nikkomycinZ, and manogepix.
Project description:A systematic approach allowing the identification of the molecular way-of-action of novel potential drugs represents the golden-tool for drug-discovery. While high-throughput screening technologies of large libraries is now well established, the assessment of the drug targets and mechanism of action is still under development. Taking advantage of the yeast model Saccharomyces cerevisiae, we herein applied BarSeq, a Next Generation Sequencing-based method to the analysis of both haploinsufficiency and homozygous fitness effects of a novel antifungal drug ('089') compared to the well-known antifungal ketoconazole. '089' was a novel compound identified in during a screen for antifungal drugs, as it was showing fungicidal effects, and able to affect the yeast fitness at the mitochondrial level (Stefanini et al., 2010. (Dissection of the Effects of Small Bicyclic Peptidomimetics on a Panel of Saccharomyces cerevisiae Mutants;.J Biol Chem, 285: 23477-23485.) Integrative bioinformatic analysis of BarSeq, whole genome expression analysis and classical biological assays identified the target and cell pathways affected by the novel antifungal. Confirmation of the effects observed in the yeast model and in pathogenic fungi further demonstrated the reliability of the multi-sided approach and the novelty of the targets and way-of-action of the new class of molecules studied representing a valuable source of novel antifungals.
Project description:Violacein is a bacterial purple pigment with antimicrobial, antiparasitic, antifungal, antiviral, and anticancer properties. We previously reported that violacein has antiproliferative activity in cervical and bladder cancer-derived cells, and also sensitizes cells to cisplatin. Currently, we report the results obtained on T24 bladder cancer cells by using quantitative differential proteomics.
Project description:Collimonas is a genus of soil bacteria which comprises three recognized species: C. fungivorans, C. pratensis and C. arenae. The bacteria belonging to this genus share the ability to lyse chitin (chitinolysis) and feed on living fungal hyphae (mycophagy), but they differ in colony morphology, physiological properties and antifungal activity. In order to gain a better insight into the genetic background underlying this phenotypic variability of collimonads, we investigated the variability in the genomic content of five strains representing the three formally recognized Collimonas species. The genomic content of four test strains was hybridized on an array representing the reference strain C. fungivorans Ter331.
Project description:In contrast to comprehensively investigated antibacterial activity of snake venoms, namely crude venoms and their selected components, little is known about antifungal properties of elapid snake venoms. In the present study, the proteome of two venoms of red spitting cobra Naja pallida (NPV) and Mozambique spitting cobra Naja mossambica (NMV) was characterized using LC-MS/MS approach and the biological activity of crude venoms against three Candida species was established.
Project description:The complex structure of the biofilm generates microenvironments which impact the fitness of the biofilm community as a whole. Contributions to fitness include the development of emergent properties resulting in the recalcitrance to external stressors such as environmental stress or drug stress in the context of a pathogen. The biofilm developed by the filamentous fungal pathogen Aspergillus fumigatus develops zones of low oxygen which contribute to a reduction in antifungal drug susceptibility, however the mechanisms driving this have remained elusive. Here we have utilized a transcriptomic approach to probe the biofilm structure in comparison to a planktonic lifestyle to identify unique biofilm transcriptional patterns. Importantly we utilized two phenotypically diverse strains. From this analysis we have identified biofilm specific gene co-expression networks as well as a ceramide synthase, designated barA, with a striking increase in transcript abundance specifically in the biofilm. Null mutants for barA in two strain backgrounds display altered biofilm morphology with some strain specific differences but interestingly do not impact virulence. Importantly we find the BarA ceramide synthase has a role in regulating susceptibility to classes of ergosterol targeting antifungal drugs. In the absence of barA, treatment with voriconazole leads to significant cellular damage in the form of lysis. Through this we have identified a novel mechanism driving antifungal drug resistance in the biofilm of filamentous fungal pathogen.