Identification and Mode of Action of a Plant Natural Product Targeting Human Fungal Pathogens
نویسندگان
چکیده
Candida albicans is a major cause of fungal diseases in humans, and its resistance to available drugs is of concern. In an attempt to identify novel antifungal agents, we initiated a small-scale screening of a library of 199 natural plant compounds (i.e., natural products [NPs]). In vitro susceptibility profiling experiments identified 33 NPs with activity against C. albicans (MIC50s ≤ 32 μg/ml). Among the selected NPs, the sterol alkaloid tomatidine was further investigated. Tomatidine originates from the tomato (Solanum lycopersicum) and exhibited high levels of fungistatic activity against Candida species (MIC50s ≤ 1 μg/ml) but no cytotoxicity against mammalian cells. Genome-wide transcriptional analysis of tomatidine-treated C. albicans cells revealed a major alteration (upregulation) in the expression of ergosterol genes, suggesting that the ergosterol pathway is targeted by this NP. Consistent with this transcriptional response, analysis of the sterol content of tomatidine-treated cells showed not only inhibition of Erg6 (C-24 sterol methyltransferase) activity but also of Erg4 (C-24 sterol reductase) activity. A forward genetic approach in Saccharomyces cerevisiae coupled with whole-genome sequencing identified 2 nonsynonymous mutations in ERG6 (amino acids D249G and G132D) responsible for tomatidine resistance. Our results therefore unambiguously identified Erg6, a C-24 sterol methyltransferase absent in mammals, to be the main direct target of tomatidine. We tested the in vivo efficacy of tomatidine in a mouse model of C. albicans systemic infection. Treatment with a nanocrystal pharmacological formulation successfully decreased the fungal burden in infected kidneys compared to the fungal burden achieved by the use of placebo and thus confirmed the potential of tomatidine as a therapeutic agent.
منابع مشابه
Fungal Plant Disease Management by Natural Essential Oils
Safaei-Farahani B. and Mostowfizade-Ghalamfarsa R. 2019. Fungal plant disease management by natural essential oils. Plant Pathology Science 8(1):24-37. DOI: 10.2982/PPS.8.1.24. Essential oils are hydrophobic, volatile and aromatic compounds that have been used as fragrances and flavors for a long time. Recent studies have shown that some plant essential oils have fungicidal effects agains...
متن کاملIdentification of volatile organic compounds of some Trichoderma species using static headspace gas chromatography-mass spectrometry
Fungi release wide spectrum of volatile organic compounds (VOCs) that belong to several chemical groups with different biochemical origins such as monoterpenes, sesquiterpenes, alcohols, aldehydes, aromatic compounds, esters, furans, ketones, sulfur and nitrogen compounds. Trichoderma species are the most studied fungal biocontrol agents and are successfully used as biofungicides and biofertili...
متن کاملFungal phytotoxins with potential herbicidal activity: chemical and biological characterization.
Covering: 2007 to 2015 Fungal phytotoxins are secondary metabolites playing an important role in the induction of disease symptoms interfering with host plant physiological processes. Although fungal pathogens represent a heavy constraint for agrarian production and for forest and environmental heritage, they can also represent an ecofriendly alternative to manage weeds. Indeed, the phytotoxins...
متن کاملIdentification of Some Molecular Traits in Fluorescent Pseudomonads with Antifungal Activity
We assessed a collection of 47 fluorescent Pseudomonas spp., some with known biological control activity against certain soil-borne phytopathogenic fungi such as, Macrophomina phaseolina, Rhizoctonia solani, Phytophthora nicotianae var. parasitica, Pythium sp. and Fusarium sp. in vitro and the potential to produce known secondary metabolites such as, siderophore, HCN and protease. The resu...
متن کاملروشهای تشخیصی بیماریهای قارچی: از دوره کلاسیک تا عصر مولکولی
Human fungal diseases are largely a 20th and 21st century’s phenomenon. Due to use of corticosteroids and antibacterial drug, medical developmenta are associated with increased risk for number of fungal disease. These nosocomial developments in invasive mycosis were paralleled over the last two decades by the human immunodeficiency virus (HIV) pandemic, which has resulted in an even larger numb...
متن کاملذخیره در منابع من
با ذخیره ی این منبع در منابع من، دسترسی به آن را برای استفاده های بعدی آسان تر کنید
عنوان ژورنال:
دوره 61 شماره
صفحات -
تاریخ انتشار 2017