Search Results (21)

In the context of the valorization of agri-food by-products, tomato (Solanum lycopersicum L.) seeds represent a protein-rich matrix containing potential bioactives. The aim of the present work is to develop a biochemical pipeline for (i) achieving high protein recovery from tomato seed, (ii) optimizing the hydrolysis with different proteases, and (iii) characterizing the resulting peptides. This approach was instrumental for obtaining and selecting the most promising peptide mixture to test for antifungal activity. To this purpose, proteins from an alkaline extraction were treated with bromelain, papain, and pancreatin, and the resulting hydrolysates were assessed for their protein/peptide profiles via SDS-PAGE, SEC-HPLC, and RP-HPLC. Bromelain hydrolysate was selected for antifungal tests due to its greater quantity of peptides, in a broader spectrum of molecular weights and polarity/hydrophobicity profiles, and higher DPPH radical scavenging activity, although all hydrolysates exhibited antioxidant properties. In vitro assays demonstrated that the bromelain-digested proteins inhibited the growth of Fusarium graminearum and F. oxysporum f.sp. lycopersici in a dose-dependent manner, with a greater effect at a concentration of 0.1 mg/mL. The findings highlight that the enzymatic hydrolysis of tomato seed protein represents a promising strategy for converting food by-products into bioactive agents with agronomic applications, supporting sustainable biotechnology and circular economy strategies. Full article

The current 2019–2021 marine pharmacology literature review provides a continuation of previous reviews covering the period 1998 to 2018. Preclinical marine pharmacology research during 2019–2021 was published by researchers in 42 countries and contributed novel mechanism-of-action pharmacology for 171 structurally characterized marine compounds. The peer-reviewed marine natural product pharmacology literature reported antibacterial, antifungal, antiprotozoal, antituberculosis, and antiviral mechanism-of-action studies for 49 compounds, 87 compounds with antidiabetic and anti-inflammatory activities that also affected the immune and nervous system, while another group of 51 compounds demonstrated novel miscellaneous mechanisms of action, which upon further investigation, may contribute to several pharmacological classes. Thus, in 2019–2021, a very active preclinical marine natural product pharmacology pipeline provided novel mechanisms of action as well as new lead chemistry for the clinical marine pharmaceutical pipeline targeting the therapy of several disease categories. Full article

Marine natural products are well-recognized as potential resources to fill the pipeline of drug leads to enter the pharmaceutical industry. In this circumstance, marine-derived fungi are one of the unique sources of bioactive secondary metabolites due to their capacity to produce diverse polyketides and peptides with unique structures and diverse biological activities. The present review covers the peptides from marine-derived fungi reported from the literature published from January 1991 to June 2023, and various scientific databases, including Elsevier, ACS publications, Taylor and Francis, Wiley Online Library, MDPI, Springer, Thieme, Bentham, ProQuest, and the Marine Pharmacology website, are used for a literature search. This review focuses on chemical characteristics, sources, and biological and pharmacological activities of 366 marine fungal peptides belonging to various classes, such as linear, cyclic, and depsipeptides. Among 30 marine-derived fungal genera, isolated from marine macro-organisms such as marine algae, sponges, coral, and mangrove plants, as well as deep sea sediments, species of Aspergillus were found to produce the highest number of peptides (174 peptides), followed by Penicillium (23 peptides), Acremonium (22 peptides), Eurotium (18 peptides), Trichoderma (18 peptides), Simplicillium (17 peptides), and Beauveria (12 peptides). The cytotoxic activity against a broad spectrum of human cancer cell lines was the predominant biological activity of the reported marine peptides (32%), whereas antibacterial, antifungal, antiviral, anti-inflammatory, and various enzyme inhibition activities ranged from 7% to 20%. In the first part of this review, the chemistry of marine peptides is discussed and followed by their biological activity. Full article

Fungal infections, named mycosis, can cause severe invasive and systemic diseases that can even lead to death. In recent years, epidemiological data have recorded an increase in cases of severe fungal infections, caused mainly by a growing number of immunocompromised patients and the emergence of fungal pathogenic forms that are increasingly resistant to antimycotic drug treatments. Consequently, an increase in the incidence of mortality due to fungal infections has also been observed. Among the most drug-resistant fungal forms are those belonging to the Candida and Aspergillus spp. Some pathogens are widespread globally, while others are endemic in some areas only. In addition, some others may represent a health threat for some specific subpopulations and not for the general public. In contrast to the extensive therapeutic armamentarium available for the antimicrobial chemotherapeutic treatment of bacteria, for fungal infections there are only a few classes of antimycotic drugs on the market, such as polyenes, azoles, echinocandins, and a few molecules are under trial. In this review, we focused on the systemic mycosis, highlighted the antifungal drug compounds available in the pipeline, and analyzed the main molecular mechanisms for the development of antifungal resistance to give a comprehensive overview and increase awareness on this growing health threat. Full article

Due to their eukaryotic heritage, the differences between a fungal pathogen’s molecular makeup and its human host are small. Therefore, the discovery and subsequent development of novel antifungal drugs are extremely challenging. Nevertheless, since the 1940s, researchers have successfully uncovered potent candidates from natural or synthetic sources. Analogs and novel formulations of these drugs enhanced the pharmacological parameters and improved overall drug efficiency. These compounds ultimately became the founding members of novel drug classes and were successfully applied in clinical settings, offering valuable and efficient treatment of mycosis for decades. Currently, only five different antifungal drug classes exist, all characterized by a unique mode of action; these are polyenes, pyrimidine analogs, azoles, allylamines, and echinocandins. The latter, being the latest addition to the antifungal armamentarium, was introduced over two decades ago. As a result of this limited arsenal, antifungal resistance development has exponentially increased and, with it, a growing healthcare crisis. In this review, we discuss the original sources of antifungal compounds, either natural or synthetic. Additionally, we summarize the existing drug classes, potential novel candidates in the clinical pipeline, and emerging non-traditional treatment options. Full article

The alarming spread and impact of multidrug-resistant Candida auris infections alongside the limited therapeutic options have prompted the development of new antifungals. These promising agents are currently in different stages of development, offering novel dosing regimens and mechanisms of action. A systematic search in MEDLINE, EMBASE, Web of Science, and Scopus up to 27 June 2022 was conducted to find relevant articles reporting data of in vitro activity and in vivo efficacy of investigational antifungals against C. auris. These included new additions to existing antifungal classes (rezafungin and opelconazole), first-in-class drugs such as ibrexafungerp, manogepix/fosmanogepix, olorofim and tetrazoles (quilseconazole, oteseconazole and VT-1598), as well as other innovative agents like ATI-2307, MGCD290 and VL-2397. From 592 articles retrieved in the primary search, 27 met the eligibility criteria. The most studied agent was manogepix/fosmanogepix (overall MIC₉₀: 0.03 mg/L), followed by ibrexafungerp (overall MIC₉₀: 1 mg/L) and rezafungin (overall MIC mode: 0.25 mg/L), while VT-1598 and ATI-2307 were the least explored drugs against C. auris. All these compounds demonstrated significant improvements in survival and reduction in tissue fungal burden on neutropenic animal models of candidemia due to C. auris. Continual efforts towards the discovery of new treatments against this multidrug-resistant fungus are essential. Full article

Onychomycosis is a common nail disease caused by fungi. The primary pathogens are dermatophytes; however, yeasts, non-dermatophyte moulds, and mixed fungal populations may also contribute to the development of a recalcitrant condition, usually accompanied by difficulties in everyday life and severe emotional stress. Treatment failure and relapse of the infection are the most frequent problems, though new issues have become the new challenges in the therapeutic approach to onychomycosis. Resistance to antifungals, an increasing number of comorbidities, and polydrug use among the ageing population are imperatives that impose a shift to safer drugs. Topical antifungals are considered less toxic and minimally interact with other drugs. The development of new topical drugs for onychomycosis is driven by the unmet need for effective agents with prolonged post-treatment disease-free time and a lack of systemic impact on the patients’ health. Efinaconazole, Tavaborole, and Luliconazole have been added to physicians’ weaponry during the last decade, though launched on the market of a limited number of countries. The pipeline is either developing new products (e.g., ME-1111 and NP213) with an appealing combination of pharmacokinetic, efficacy, and safety properties or reformulating old, well-known drugs (Terbinafine and Amphotericin B) by using new excipients as penetration enhancers. Full article

Coumarins are a structurally varied set of 2H-chromen-2-one compounds categorized also as members of the benzopyrone group of secondary metabolites. Coumarin derivatives attract interest owing to their wide practical application and the unique reactivity of fused benzene and pyrone ring systems in molecular structure. Coumarins have their own specific fingerprints as antiviral, antimicrobial, antioxidant, anti-inflammatory, antiadipogenic, cytotoxic, apoptosis, antitumor, antitubercular, and cytotoxicity agents. Natural products have played an essential role in filling the pharmaceutical pipeline for thousands of years. Biological effects of natural coumarins have laid the basis of low-toxic and highly effective drugs. Presently, more than 1300 coumarins have been identified in plants, bacteria, and fungi. Fungi as cultivated microbes have provided many of the nature-inspired syntheses of chemically diverse drugs. Endophytic fungi bioactivities attract interest, with applications in fields as diverse as cancer and neuronal injury or degeneration, microbial and parasitic infections, and others. Fungal mycelia produce several classes of bioactive molecules, including a wide group of coumarins. Of promise are further studies of conditions and products of the natural and synthetic coumarins’ biotransformation by the fungal cultures, aimed at solving the urgent problem of searching for materials for biomedical engineering. The present review evaluates the fungal coumarins, their structure-related peculiarities, and their future therapeutic potential. Special emphasis has been placed on the coumarins successfully bioprospected from fungi, whereas an industry demand for the same coumarins earlier found in plants has faced hurdles. Considerable attention has also been paid to some aspects of the molecular mechanisms underlying the coumarins’ biological activity. The compounds are selected and grouped according to their cytotoxic, anticancer, antibacterial, antifungal, and miscellaneous effects. Full article

The utility of clinically available antifungals is limited by their narrow spectrum of activity, high toxicity, and emerging resistance. Antifungal drug discovery has always been a challenging area, since fungi and their human host are eukaryotes, making it difficult to identify unique targets for antifungals. Novel antifungals in clinical development include first-in-class agents, new structures for an established target, and formulation modifications to marketed antifungals, in addition to repurposed agents. Membrane interacting peptides and aromatherapy are gaining increased attention in the field. Immunotherapy is another promising treatment option, with antifungal antibodies advancing into clinical trials. Novel targets for antifungal therapy are also being discovered, allowing the design of new promising agents that may overcome the resistance issue. In this mini review, we will summarize the current status of antifungal drug pipelines in clinical stages, and the most recent advancements in preclinical antifungal drug development, with special focus on their chemistry. Full article

Multiple outbreaks of epidemic and pandemic viral diseases have occurred in the last 20 years, including those caused by Ebola virus, Zika virus, and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The emergence or re-emergence of such diseases has revealed the deficiency in our pipeline for the discovery and development of antiviral drugs. One promising solution is the extensive library of antimicrobial peptides (AMPs) produced by all eukaryotic organisms. AMPs are widely known for their activity against bacteria, but many possess additional antifungal, antiparasitic, insecticidal, anticancer, or antiviral activities. AMPs could therefore be suitable as leads for the development of new peptide-based antiviral drugs. Sixty therapeutic peptides had been approved by the end of 2018, with at least another 150 in preclinical or clinical development. Peptides undergoing clinical trials include analogs, mimetics, and natural AMPs. The advantages of AMPs include novel mechanisms of action that hinder the evolution of resistance, low molecular weight, low toxicity toward human cells but high specificity and efficacy, the latter enhanced by the optimization of AMP sequences. In this opinion article, we summarize the evidence supporting the efficacy of antiviral AMPs and discuss their potential to treat emerging viral diseases including COVID-19. Full article

Candida auris is a multidrug-resistant pathogen that represents a serious public health threat due to its rapid global emergence, increasing incidence of healthcare-associated outbreaks, and high rates of antifungal resistance. Whole-genome sequencing and genomic surveillance have the potential to bolster C. auris surveillance networks moving forward. Laboratories conducting genomic surveillance need to be able to compare analyses from various national and international surveillance partners to ensure that results are mutually trusted and understood. Therefore, we established an empirical outbreak benchmark dataset consisting of 23 C. auris genomes to help validate comparisons of genomic analyses and facilitate communication among surveillance networks. Our outbreak benchmark dataset represents a polyclonal phylogeny with three subclades. The genomes in this dataset are from well-vetted studies that are supported by multiple lines of evidence, which demonstrate that the whole-genome sequencing data, phylogenetic tree, and epidemiological data are all in agreement. This C. auris benchmark set allows for standardized comparisons of phylogenomic pipelines, ultimately promoting effective C. auris collaborations. Full article

The review of the 2016–2017 marine pharmacology literature was prepared in a manner similar as the 10 prior reviews of this series. Preclinical marine pharmacology research during 2016–2017 assessed 313 marine compounds with novel pharmacology reported by a growing number of investigators from 54 countries. The peer-reviewed literature reported antibacterial, antifungal, antiprotozoal, antituberculosis, and antiviral activities for 123 marine natural products, 111 marine compounds with antidiabetic and anti-inflammatory activities as well as affecting the immune and nervous system, while in contrast 79 marine compounds displayed miscellaneous mechanisms of action which upon further investigation may contribute to several pharmacological classes. Therefore, in 2016–2017, the preclinical marine natural product pharmacology pipeline generated both novel pharmacology as well as potentially new lead compounds for the growing clinical marine pharmaceutical pipeline, and thus sustained with its contributions the global research for novel and effective therapeutic strategies for multiple disease categories. Full article

The success of antifungal therapies is often hindered by the limited number of available drugs. To close the gap in the antifungal pipeline, the search of novel leads is of primary importance, and here the exploration of neglected plants has great promise for the discovery of new principles. Through bioassay-guided isolation, uliginosin B and five new dimeric acylphloroglucinols (uliginosins C-D, and 3′prenyl uliginosins B-D), besides cembrenoids, have been isolated from the lipophilic extract of Hypericum mexicanum. Their structures were elucidated by a combination of Liquid Chromatography - Mass Spectrometry LC-MS and Nuclear Magnetic Resonance (NMR) measurements. The compounds showed strong anti-Candida activity, also against fluconazole-resistant strains, with fungal growth inhibition properties at concentrations ranging from 3 to 32 µM, and reduced or absent cytotoxicity against human cell lines. A chemogenomic screen of 3′prenyl uliginosin B revealed target genes that are important for cell cycle regulation and cytoskeleton assembly in fungi. Taken together, our study suggests dimeric acylphloroglucinols as potential candidates for the development of alternative antifungal therapies. Full article

The high incidence of fungal infections has become a worrisome public health issue, having been aggravated by an increase in host predisposition factors. Despite all the drugs available on the market to treat these diseases, their efficiency is questionable, and their side effects cannot be neglected. Bearing that in mind, it is of upmost importance to synthetize new and innovative carriers for these medicines not only to fight emerging fungal infections but also to avert the increase in drug-resistant strains. Although it has revealed to be a difficult job, new nano-based drug delivery systems and even new cellular targets and compounds with antifungal potential are now being investigated. This article will provide a summary of the state-of-the-art strategies that have been studied in order to improve antifungal therapy and reduce adverse effects of conventional drugs. The bidirectional relationship between Mycology and Nanotechnology will be also explained. Furthermore, the article will focus on new compounds from the marine environment which have a proven antifungal potential and may act as platforms to discover drug-like characteristics, highlighting the challenges of the translation of these natural compounds into the clinical pipeline. Full article

Alkyl quinolone has been proven to be a privileged scaffold in the antimicrobial drug discovery pipeline. In this study, a series of new 4-hydroxy-2-quinolinone analogs containing a long alkyl side chain at C-3 and a broad range of substituents on the C-6 and C-7 positions were synthesized. The antibacterial and antifungal activities of these analogs against Staphylococcus aureus, Escherichia coli, and Aspergillus flavus were investigated. The structure-activity relationship study revealed that the length of the alkyl chain, as well as the type of substituent, has a dramatic impact on the antimicrobial activities. Particularly, the brominated analogs 3j with a nonyl side chain exhibited exceptional antifungal activities against A. flavus (half maximal inhibitory concentration (IC₅₀) = 1.05 µg/mL), which surpassed that of the amphotericin B used as a positive control. The antibacterial activity against S. aureus, although not as potent, showed a similar trend to the antifungal activity. The data suggest that the 4-hydroxy-2-quinolone is a promising framework for the further development of new antimicrobial agents, especially for antifungal treatment. Full article