Antifungals Campoy, Sonia; Adrio, José L.
Biochemical pharmacology,
06/2017, Letnik:
133
Journal Article
Recenzirano
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The need for new antifungal agents is undeniable. Current therapeutic choices for the treatment of invasive fungal infections are limited to three classes of drugs. Most used ...antifungal agents are not completely effective due to the development of resistance, host toxicity and undesirable side effects that limit their use in medical practice. Invasive fungal infections have significantly increased over the last decades and the mortality rates remain unacceptably high. More threatening, new resistance patterns have been observed including simultaneous resistance to different antifungal classes.
In the last years, deeper insights into the molecular mechanisms for fungal resistance and virulence have yielded some new potential targets for antifungal therapeutics. Chemical genomics-based screenings, high throughput screenings of natural products and repurposing of approved drugs are some of the approaches being followed for the discovery of new antifungal molecules. However, despite the emerging need for effective antifungal agents, the current pipeline contains only a few promising molecules, with novel modes of action, in early clinical development stages.
The epidemiology of invasive fungal infections is changing, with new populations at risk and the emergence of resistance caused by the selective pressure from increased usage of antifungal agents in ...prophylaxis, empiric therapy, and agriculture. Limited antifungal therapeutic options are further challenged by drug–drug interactions, toxicity, and constraints in administration routes. Despite the need for more antifungal drug options, no new classes of antifungal drugs have become available over the last 2 decades, and only one single new agent from a known antifungal class has been approved in the last decade. Nevertheless, there is hope on the horizon, with a number of new antifungal classes in late-stage clinical development. In this review, we describe the mechanisms of drug resistance employed by fungi and extensively discuss the most promising drugs in development, including fosmanogepix (a novel Gwt1 enzyme inhibitor), ibrexafungerp (a first-in-class triterpenoid), olorofim (a novel dihyroorotate dehydrogenase enzyme inhibitor), opelconazole (a novel triazole optimized for inhalation), and rezafungin (an echinocandin designed to be dosed once weekly). We focus on the mechanism of action and pharmacokinetics, as well as the spectrum of activity and stages of clinical development. We also highlight the potential future role of these drugs and unmet needs.
Artemisia vulgaris is an enormously useful aromatic plant known for its insecticidal, antifungal, parasiticidal, and medicinal values. The main aim of this study is to investigate phytochemical ...contents and the potential antimicrobial activities of Artemisia vulgaris essential oil (AVEO) from the fresh leaves of A. vulgaris grown in Manipur. The AVEO isolated by hydro-distillation from A. vulgaris were analyzed by gas chromatography/mass spectrometry and solid-phase microextraction-GC/MS to describe their volatile chemical profile. There were 47 components identified in the AVEO by GC/MS, amounting to 97.66% of the total composition, while 97.35% were identified by SPME-GC/MS. The prominent compounds present in AVEO analyzed by direct injection and SPME methods are found to be eucalyptol (29.91% and 43.70%), sabinene (8.44% and 8.86%), endo-Borneol (8.24% and 4.76%), 2,7-Dimethyl-2,6-octadien-4-ol (6.76% and 4.24%), and 10-epi-γ-Eudesmol (6.50% and 3.09%). The consolidated component in the leaf volatiles comes to the terms of monoterpenes. The AVEO exhibits antimicrobial activities against fungal pathogens such as Sclerotium oryzae (ITCC 4107) and Fusarium oxysporum (MTCC 9913) and bacterial cultures such as Bacillus cereus (ATCC 13061) and Staphylococcus aureus (ATCC 25923). The percent inhibition of AVEO against the S. oryzae and F. oxysporum was found up to 50.3% and 33.13%, respectively. The MIC and MBC of the essential oil tested for B. cereus and S. aureus were found to be (0.3%, 0.63%) and (0.63%, 2.5%), respectively. Finally, the results revealed that the AVEO characterized by the hydro-distillation and SPME extraction yielded the same chemical profile and showed potent antimicrobial activities. Further research into A. vulgaris's antibacterial properties can be performed in order to use it as a source for natural antimicrobial medications.
Currently the discovery and development of potent β-glucuronidase inhibitors is an active area of research due to the observation that increased activity of this enzyme is associated with many ...pathological conditions, such as colon cancer, renal diseases, and infections of the urinary tract. In this study, twenty-seven 2-aminopyrimidine derivatives 1-27 were synthesized by fusion of 2-amino-4,6-dichloropyrimidine with a variety of amines in the presence of triethylamine without using any solvent and catalyst, in good to excellent yields. All synthesized compounds were characterized by EI-MS, HREI-MS and NMR spectroscopy. Compounds 1-27 were then evaluated for their β-glucuronidase inhibitory activity, and among them, compound 24 (ICsub.50 = 2.8 ± 0.10 µM) showed an activity much superior to standard D-saccharic acid 1,4-lactone (ICsub.50 = 45.75 ± 2.16 µM). To predict the binding mode of the substrate and β-glucuronidase, in silico study was performed. Conclusively, this study has identified a potent β-glucuronidase inhibitor that deserves to be further studied for the development of pharmaceutical products.
To search for efficient agricultural antifungal lead compounds, 39 Chimonanthus praecox derivatives were designed, synthesized, and evaluated for their antifungal activities. The structures of target ...compounds were fully characterized by sup.1H NMR, sup.13C NMR, and MS spectra. The preliminary bioassays revealed that some compounds exhibited excellent antifungal activities in vitro. For example, the minimum inhibitory concentration (MIC) of compound b15 against Phytophthora infestans was 1.95 µg mLsup.−1, and the minimum inhibitory concentration (MIC) of compound b17 against Sclerotinia sclerotiorum was 1.95 µg mLsup.−1. Therefore, compounds b15 and b17 were identified as the most promising candidates for further study.
Fungal infections are a major contributor to infectious disease-related deaths across the globe. Candida species are among the most common causes of invasive mycotic disease, with Candida albicans ...reigning as the leading cause of invasive candidiasis. Given that fungi are eukaryotes like their human host, the number of unique molecular targets that can be exploited for antifungal development remains limited. Currently, there are only three major classes of drugs approved for the treatment of invasive mycoses, and the efficacy of these agents is compromised by the development of drug resistance in pathogen populations. Notably, the emergence of additional drug-resistant species, such as Candida auris and Candida glabrata, further threatens the limited armamentarium of antifungals available to treat these serious infections. Here, we describe our current arsenal of antifungals and elaborate on the resistance mechanisms Candida species possess that render them recalcitrant to therapeutic intervention. Finally, we highlight some of the most promising therapeutic strategies that may help combat antifungal resistance, including combination therapy, targeting fungal-virulence traits, and modulating host immunity. Overall, a thorough understanding of the mechanistic principles governing antifungal drug resistance is fundamental for the development of novel therapeutics to combat current and emerging fungal threats.
New antifungals are urgently needed to combat invasive fungal infections, due to limited types of available antifungal drugs and frequently encountered side effects, as well as the quick emergence of ...drug‐resistance. We previously developed amine‐pendent poly(2‐oxazoline)s (POXs) as synthetic mimics of host defense peptides (HDPs) to have antibacterial properties, but with poor antifungal activity. Hereby, we report the finding of short guanidinium‐pendent POXs, inspired by cell‐penetrating peptides, as synthetic mimics of HDPs to display potent antifungal activity, superior mammalian cells versus fungi selectivity, and strong therapeutic efficacy in treating local and systemic fungal infections. Moreover, the unique antifungal mechanism of fungal cell membrane penetration and organelle disruption explains the insusceptibility of POXs to antifungal resistance. The easy synthesis and structural diversity of POXs imply their potential as a class of promising antifungal agents.
Inspired by cell‐penetrating peptides, guanidinium‐pendent poly(2‐oxazoline)s were designed as synthetic mimics of host defense peptides to display potent antifungal properties, owing to the enhanced penetrating efficiency into fungal cells. Short guanidinium‐pendent poly(2‐oxazoline)s display strong therapeutic potential as a class of promising antifungal agents.
New antifungal drugs are urgently needed to address the emergence and transcontinental spread of fungal infectious diseases, such as pandrug-resistant
Leveraging the microbiomes of marine animals and ...cutting-edge metabolomics and genomic tools, we identified encouraging lead antifungal molecules with in vivo efficacy. The most promising lead, turbinmicin, displays potent in vitro and mouse-model efficacy toward multiple-drug-resistant fungal pathogens, exhibits a wide safety index, and functions through a fungal-specific mode of action, targeting Sec14 of the vesicular trafficking pathway. The efficacy, safety, and mode of action distinct from other antifungal drugs make turbinmicin a highly promising antifungal drug lead to help address devastating global fungal pathogens such as
Use of silver and silver salts is as old as human civilization but the fabrication of silver nanoparticles (Ag NPs) has only recently been recognized. They have been specifically used in agriculture ...and medicine as antibacterial, antifungal and antioxidants. It has been demonstrated that Ag NPs arrest the growth and multiplication of many bacteria such as Bacillus cereus, Staphylococcus aureus, Citrobacter koseri, Salmonella typhii, Pseudomonas aeruginosa, Escherichia coli, Klebsiella pneumonia, Vibrio parahaemolyticus and fungus Candida albicans by binding Ag/Ag
with the biomolecules present in the microbial cells. It has been suggested that Ag NPs produce reactive oxygen species and free radicals which cause apoptosis leading to cell death preventing their replication. Since Ag NPs are smaller than the microorganisms, they diffuse into cell and rupture the cell wall which has been shown from SEM and TEM images of the suspension containing nanoparticles and pathogens. It has also been shown that smaller nanoparticles are more toxic than the bigger ones. Ag NPs are also used in packaging to prevent damage of food products by pathogens. The toxicity of Ag NPs is dependent on the size, concentration, pH of the medium and exposure time to pathogens.
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