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Future Microbiology Nov 2023Tweetable abstract Repurposing existing drugs for fungal infections has demonstrated potential in both and animal models, but there are still obstacles to overcome for...
Tweetable abstract Repurposing existing drugs for fungal infections has demonstrated potential in both and animal models, but there are still obstacles to overcome for clinical application. #antifungal #drugrepurposing #fungalinfections.
Topics: Animals; Drug Repositioning; Antifungal Agents; Mycoses
PubMed: 37721174
DOI: 10.2217/fmb-2023-0108 -
Journal of Chemical Information and... May 2024Antifungal peptides (AFPs) are emerging as promising candidates for advanced antifungal therapies because of their broad-spectrum efficacy and reduced resistance...
Antifungal peptides (AFPs) are emerging as promising candidates for advanced antifungal therapies because of their broad-spectrum efficacy and reduced resistance development. design of AFPs, however, remains challenging, due to the lack of an efficient and well-validated quantitative assessment of antifungal activity. This study introduced an AFP design approach that leverages an innovative quantitative metric, named the antifungal index (AFI), through a three-step process, , segmentation, single-point mutation, and global multipoint optimization. An exhaustive search of 100 putative AFP sequences indicated that random modifications without guidance only have a 5.97-20.24% chance of enhancing antifungal activity. Analysis of the search results revealed that (1) N-terminus truncation is more effective in enhancing antifungal activity than the modifications at the C-terminus or both ends, (2) introducing the amino acids within the 10-60% sequence region that enhance aromaticity and hydrophobicity are more effective in increasing antifungal efficacy, and (3) incorporating alanine, cysteine, and phenylalanine during multiple point mutations has a synergistic effect on enhancing antifungal activity. Subsequently, 28 designed peptides were synthesized and tested against four typical fungal strains. The success rate for developing promising AFPs, with a minimal inhibitory concentration of ≤5.00 μM, was an impressive 82.14%. The predictive and design tool is accessible at https://antifungipept.chemoinfolab.com.
Topics: Antifungal Agents; Drug Design; Microbial Sensitivity Tests; Computer Simulation; Amino Acid Sequence; Peptides; Fungi
PubMed: 38743449
DOI: 10.1021/acs.jcim.4c00142 -
Journal of Ethnopharmacology Jan 2024Cannabis sativa L. (Cannabaceae) is a plant native to Eastern Asia spread throughout the world because of its medicinal properties. Despite being used for thousands of...
ETHNOPHARMACOLOGICAL RELEVANCE
Cannabis sativa L. (Cannabaceae) is a plant native to Eastern Asia spread throughout the world because of its medicinal properties. Despite being used for thousands of years as a palliative therapeutic agent for many pathologies, in many countries research on its effects and properties could only be carried out in recent years, after its legalization.
AIMS OF THE STUDY
Increasing resistance to traditional antimicrobial agents demands finding new strategies to fight against microbial infections in medical therapy and agricultural activities. Upon legalization in many countries, Cannabis sativa is gaining attention as a new source of active components, and the evidence for new applications of these compounds is constantly increasing.
METHODS
Extracts from five different varieties ofCannabis sativa were performed and their cannabinoids and terpenes profiles were determined by liquid and gas chromatography. Antimicrobial and antifungal activities against Gram (+) and Gram (-) bacteria, yeast and phytopathogen fungus were measured. To analyze a possible action mechanism, cell viability of bacteria and yeast was assessed by propidium iodide stain.
RESULTS
Cannabis varieties were grouped into chemotype I and II as a consequence of their cannabidiol (CBD) or tetrahydrocannabinol (THC) content. The terpenes profile was different in quantity and quality among varieties, with (-)b-pinene, b-myrcene, p-cymene and b-caryophyllene being present in all plants. All cannabis varieties were effective to different degree against Gram (+) and Gram (-) bacteria as well as on spore germination and vegetative development of phytopathogenic fungi. These effects were not correlated to the content of major cannabinoids such as CBD or THC, but with the presence of a complex terpenes profile. The effectiveness of the extracts allowed to reduce the necessary doses of a widely used commercial antifungal to prevent the development of fungal spores.
CONCLUSION
All the extracts of the analysed cannabis varieties showed antibacterial and antifungal activities. In addition, plants belonging to the same chemotype showed different antimicrobial activity, demonstrating that the classification of cannabis strains based solely on THC and CBD content is not sufficient to justify their biological activities and that other compounds present in the extracts are involved in their action against pathogens. Cannabis extracts act in synergy with chemical fungicides, allowing to reduce its doses.
Topics: Cannabis; Antifungal Agents; Saccharomyces cerevisiae; Cannabinoids; Cannabidiol; Terpenes; Plant Extracts; Anti-Bacterial Agents
PubMed: 37400009
DOI: 10.1016/j.jep.2023.116839 -
MBio Aug 2023The fungal pathogen represents a severe threat to hospitalized patients. Its resistance to multiple classes of antifungal drugs and ability to spread and resist...
The fungal pathogen represents a severe threat to hospitalized patients. Its resistance to multiple classes of antifungal drugs and ability to spread and resist decontamination in healthcare settings make it especially dangerous. We screened 1,990 clinically approved and late-stage investigational compounds for the potential to be repurposed as antifungal drugs targeting and narrowed our focus to five Food and Drug Administration (FDA)-approved compounds with inhibitory concentrations under 10 µM for and significantly lower toxicity to three human cell lines. These compounds, some of which had been previously identified in independent screens, include three dihalogenated 8-hydroxyquinolines: broxyquinoline, chloroxine, and clioquinol. A subsequent structure-activity study of 32 quinoline derivatives found that 8-hydroxyquinolines, especially those dihalogenated at the C5 and C7 positions, were the most effective inhibitors of . To pursue these compounds further, we exposed to clioquinol in an extended experimental evolution study and found that developed only twofold to fivefold resistance to the compound. DNA sequencing of resistant strains and subsequent verification by directed mutation in naive strains revealed that resistance was due to mutations in the transcriptional regulator (causing upregulation of the drug transporter ) and in the drug transporter . These mutations had only modest effects on resistance to traditional antifungal agents, and the mutation rendered more susceptible to posaconazole. This observation raises the possibility that a combination treatment involving an 8-hydroxyquinoline and posaconazole might prevent from developing resistance to this established antifungal agent. IMPORTANCE The rapidly emerging fungal pathogen represents a growing threat to hospitalized patients, in part due to frequent resistance to multiple classes of antifungal drugs. We identify a class of compounds, the dihalogenated 8-hydroxyquinolines, with broad fungistatic ability against a diverse collection of 13 strains of . Although this compound has been identified in previous screens, we extended the analysis by showing that developed only modest twofold to fivefold increases in resistance to this class of compounds despite long-term exposure; a noticeable difference from the 30- to 500-fold increases in resistance reported for similar studies with commonly used antifungal drugs. We also identify the mutations underlying the resistance. These results suggest that the dihalogenated 8-hydroxyquinolines are working inside the fungal cell and should be developed further to combat and other fungal pathogens. Lohse and colleagues characterize a class of compounds that inhibit the fungal pathogen . Unlike many other antifungal drugs, does not readily develop resistance to this class of compounds.
Topics: Humans; Antifungal Agents; Candida auris; Candida; Clioquinol; Membrane Transport Proteins; Microbial Sensitivity Tests; Drug Resistance, Fungal
PubMed: 37493629
DOI: 10.1128/mbio.01376-23 -
Journal of Agricultural and Food... Nov 2023Sunflower ( L.) is cultivated around the world as an oil crop, and its receptacle is the byproduct and is usually deemed to be an agro-industrial waste. Then,...
Sunflower ( L.) is cultivated around the world as an oil crop, and its receptacle is the byproduct and is usually deemed to be an agro-industrial waste. Then, phytochemical constituents and antifungal bioactivity of the sunflower receptacle against phytopathogenic fungi were investigated. As a result, 17 diterpenoids including 4 new compounds were isolated, and most of them showed potential antifungal activity against , in which compounds , , , and exhibited better inhibitory effect with the minimum inhibitory concentration values of 0.05-0.1 mg/mL. Meanwhile, four antifungal diterpenoids destructed plasma membrane integrity, suspended the biofilm formation ability, and increased the extravasation of cellular contents of . Moreover, the EtOAc extract of sunflower receptacle could keep 42.9% of blueberries from the invasion of at 1.6 mg/mL. The finding suggested that sunflower receptacle might be a biocontrol agent for preventing fruit from postharvest diseases.
Topics: Antifungal Agents; Helianthus; Diterpenes; Fruit; Cell Membrane; Botrytis; Plant Diseases
PubMed: 37877578
DOI: 10.1021/acs.jafc.3c05553 -
Annual Review of Microbiology Sep 2023Fungal-mediated disease progression and antifungal drug efficacy are significantly impacted by the dynamic infection microenvironment. At the site of infection, oxygen... (Review)
Review
Fungal-mediated disease progression and antifungal drug efficacy are significantly impacted by the dynamic infection microenvironment. At the site of infection, oxygen often becomes limiting and induces a hypoxia response in both the fungal pathogen and host cells. The fungal hypoxia response impacts several important aspects of fungal biology that contribute to pathogenesis, virulence, antifungal drug susceptibility, and ultimately infection outcomes. In this review, we summarize recent advances in understanding the molecular mechanisms of the hypoxia response in the most common human fungal pathogens, discuss potential therapeutic opportunities, and highlight important areas for future research.
Topics: Humans; Antifungal Agents; Hypoxia; Virulence; Disease Progression
PubMed: 37713457
DOI: 10.1146/annurev-micro-032521-021745 -
Revista Espanola de Quimioterapia :... Nov 2023New antifungal agents are needed to overcome limitations of available ones such as poor pharmacokinetic traits, toxicity, drug-drug interactions, limited clinical... (Review)
Review
New antifungal agents are needed to overcome limitations of available ones such as poor pharmacokinetic traits, toxicity, drug-drug interactions, limited clinical efficacy, and emerging antifungal resistance. New antifungal drugs belong to well-known families (azoles, polyenes, or beta-d-glucan synthase inhibitors) or to drug families showing completely new mechanisms of action. Some drugs have a head start in terms of potential to reach the clinical setting and are here reviewed.
Topics: Humans; Antifungal Agents; Mycoses; Azoles; Drug Resistance, Fungal; Polyenes
PubMed: 37997874
DOI: 10.37201/req/s01.14.2023 -
Brazilian Journal of Microbiology :... Sep 2023Fungal infections are now becoming a hazard to individuals which has paved the way for research to expand the therapeutic options available. Recent advances in drug... (Review)
Review
Fungal infections are now becoming a hazard to individuals which has paved the way for research to expand the therapeutic options available. Recent advances in drug design and compound screening have also increased the pace of the development of antifungal drugs. Although several novel potential molecules are reported, those discoveries have yet to be translated from bench to bedside. Polyenes, azoles, echinocandins, and flucytosine are among the few antifungal agents that are available for the treatment of fungal infections, but such conventional therapies show certain limitations like toxicity, drug interactions, and the development of resistance which limits the utility of existing antifungals, contributing to significant mortality and morbidity. This review article focuses on the existing therapies, the challenges associated with them, and the development of new therapies, including the ongoing and recent clinical trials, for the treatment of fungal infections. Advancements in antifungal treatment: a graphical overview of drug development, adverse effects, and future prospects.
Topics: Humans; Antifungal Agents; Mycoses; Echinocandins; Azoles; Drug Development; Drug Resistance, Fungal
PubMed: 37219748
DOI: 10.1007/s42770-023-00999-z -
Journal of Agricultural and Food... Sep 2023, a genus with more than 400 species, has a long history of use as an industrial bioreactor, biofertilizer, and biocontrol agent. It is considered a significant source... (Review)
Review
, a genus with more than 400 species, has a long history of use as an industrial bioreactor, biofertilizer, and biocontrol agent. It is considered a significant source of secondary metabolites (SMs) that possess unique structural features and a wide range of bioactivities. In recent years, numerous secondary metabolites of , including terpenoids, polyketides, peptides, alkaloids, and steroids, have been identified. Most of these SMs displayed antimicrobial, cytotoxic, and antifungal effects. This review focuses on the structural diversity, biological activities, and structure-activity relationships (SARs) of the SMs isolated from covered from 2018 to 2022. This study provides insights into the exploration and utilization of bioactive compounds from species in the agriculture or pharmaceutical industry.
Topics: Trichoderma; Agriculture; Antifungal Agents; Bioreactors; Industry
PubMed: 37684097
DOI: 10.1021/acs.jafc.3c04540 -
Current Microbiology Dec 2023In the recent years, occurrence of candidiasis has increased drastically which leads to significant mortality and morbidity mainly in immune compromised patients....
In the recent years, occurrence of candidiasis has increased drastically which leads to significant mortality and morbidity mainly in immune compromised patients. Glucosinolate (GLS) derivatives are reported to have antifungal activities. Ethyl isothiocyanate (EITC) and its antifungal activity and mechanism of action is still unclear against Candida albicans. The present work was designed to get a mechanistic insight in to the anti-Candida efficacy of EITC through in vitro and in vivo studies. EITC inhibited C. albicans planktonic growth at 0.5 mg/ml and virulence factors like yeast to hyphal form morphogenesis (0.0312 mg/ml), adhesion to polystyrene surface (0.0312 mg/ml) and biofilm formation (developing biofilm at 2 mg/ml and mature biofilm at 0.5 mg/ml) effectively. EITC blocked ergosterol biosynthesis and arrested C. albicans cells at S-phase. EITC caused ROS-dependent cellular death and nuclear or DNA fragmentation. EITC at 0.0312 mg/ml concentration regulated the expression of genes involved in the signal transduction pathway and inhibited yeast to hyphal form morphogenesis by upregulating TUP1, MIG1, and NRG1 by 3.10, 5.84 and 2.64-fold, respectively and downregulating PDE2 and CEK1 genes by 15.38 and 2.10-fold, respectively. EITC has showed haemolytic activity at 0.5 mg/ml concentration. In vivo study in silk worm model showed that EITC has toxicity to C. albicans at 0.5 mg/ml concentration. Thus, from present study we conclude that EITC has antifungal activity and to reduce its MIC and toxicity, combination study with other antifungal drugs need to be done. EITC and its combinations might be used as alternative therapeutics for the prevention and treatment of C. albicans infections.
Topics: Humans; Candida albicans; Antifungal Agents; Candidiasis; Isothiocyanates; Biofilms
PubMed: 38051343
DOI: 10.1007/s00284-023-03542-3