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Cytotoxic cytochalasans from cultures of the fungus Metarhizium brunneum TBRC-BCC 79240.

ABSTRACT: Fourteen new cytochalasans, brunnesins A-N (1-14), along with eleven known compounds, were isolated from the culture extracts of the insect pathogenic fungus Metarhizium brunneum strain TBRC-BCC 79240. The compound structures were established by spectroscopy, X-ray diffraction analysis, and electronic circular dichroism. Compound 4 exhibited antiproliferative activity against all cell lines tested (mammalian), with 50% inhibition concentration (IC₅₀) values ranging from 2.09 to 16.8 μg mL^-1. Compounds 6 and 16 were shown to be bioactive only against non-cancerous Vero cells (IC₅₀ 4.03 and 0.637 μg mL^-1, respectively) whereas compounds 9 and 12 were bioactive only against NCI-H187 small-cell lung cancer cells (IC₅₀ 18.59 and 18.54 μg mL^-1, respectively). Compounds 7, 13, and 14 showed cytotoxicity against NCI-H187 and Vero cell lines with IC₅₀ values ranging from 3.98-44.81 μg mL^-1.

SUBMITTER: Kornsakulkarn J

PROVIDER: S-EPMC10071300 | biostudies-literature | 2023 Apr

REPOSITORIES: biostudies-literature

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Cytotoxic cytochalasans from cultures of the fungus Metarhizium brunneum TBRC-BCC 79240.

Kornsakulkarn Jittra J Auncharoen Patchanee P Khonsanit Artit A Boonyuen Nattawut N Thongpanchang Chawanee C

RSC advances 20230404 16

Fourteen new cytochalasans, brunnesins A-N (1-14), along with eleven known compounds, were isolated from the culture extracts of the insect pathogenic fungus Metarhizium brunneum strain TBRC-BCC 79240. The compound structures were established by spectroscopy, X-ray diffraction analysis, and electronic circular dichroism. Compound 4 exhibited antiproliferative activity against all cell lines tested (mammalian), with 50% inhibition concentration (IC50) values ranging from 2.09 to ...[more]

PMID: 37025662

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Project description:Ergot alkaloids are important specialized fungal metabolites that are used to make potent pharmaceuticals for neurological diseases and disorders. Lysergic acid (LA) and dihydrolysergic acid (DHLA) are desirable lead compounds for pharmaceutical semisynthesis but are typically transient intermediates in the ergot alkaloid and dihydroergot alkaloid pathways. Previous work with Neosartorya fumigata demonstrated strategies to produce these compounds as pathway end products, but their percent yield (percentage of molecules in product state as opposed to precursor state) was low. Moreover, ergot alkaloids in N. fumigata are typically retained in the fungus as opposed to being secreted. We used clustered regularly interspaced short palindromic repeat (CRISPR)-CRISPR-associated protein 9 (Cas9) and heterologous expression approaches to engineer these compounds in Metarhizium brunneum, representing an alternate expression host from a different lineage of fungi. The relative percent yields of LA (86.9%) and DHLA (72.8%) were much higher than those calculated here for previously engineered strains of N. fumigata (2.6% and 2.0%, respectively). Secretion of these alkaloids also was measured, with averages of 98.4% of LA and 87.5% of DHLA being secreted into the growth medium; both values were significantly higher than those measured for the N. fumigata derivatives (both of which were less than 5.6% secreted). We used a similar approach to engineer a novel dihydroergot alkaloid in M. brunneum and, through high-performance liquid chromatography-mass spectrometry (LC-MS) analyses, provisionally identified it as the dihydrogenated form of lysergic acid α-hydroxyethylamide (dihydro-LAH). The engineering of these strains provides a strategy for producing novel and pharmaceutically important chemicals in a fungus more suitable for their production.IMPORTANCE Ergot alkaloids derived from LA or DHLA are the bases for numerous pharmaceuticals with applications in the treatment of dementia, migraines, hyperprolactinemia, and other conditions. However, extraction of ergot alkaloids from natural sources is inefficient, and their chemical synthesis is expensive. The ability to control and redirect ergot alkaloid synthesis in fungi may allow more efficient production of these important chemicals and facilitate research on novel derivatives. Our results show that Metarhizium brunneum can be engineered to efficiently produce and secrete LA and DHLA and, also, to produce a novel derivative of DHLA not previously found in nature. The engineering of dihydroergot alkaloids, including a novel species, is important because very few natural sources of these compounds are known. Our approach establishes a platform with which to use M. brunneum to study the production of other ergot alkaloids, specifically those classified as lysergic acid amides and dihydroergot alkaloids.

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Dataset Information

Cytotoxic cytochalasans from cultures of the fungus Metarhizium brunneum TBRC-BCC 79240.

Publications

Cytotoxic cytochalasans from cultures of the fungus <i>Metarhizium brunneum</i> TBRC-BCC 79240.

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