Epigenetic Tailoring for the Production of Anti-Infective Cytosporones from the Marine Fungus Leucostoma persoonii

Abstract

Recent genomic studies have demonstrated that fungi can possess gene clusters encoding for the production of previously unobserved secondary metabolites. Activation of these attenuated or silenced genes to obtain either improved titers of known compounds or new ones altogether has been a subject of considerable interest. In our efforts to discover new chemotypes that are effective against infectious diseases, including malaria and methicillin-resistant Staphylococcus aureus (MRSA), we have isolated a strain of marine fungus, Leucostoma persoonii, that produces bioactive cytosporones. Epigenetic modifiers employed to activate secondary metabolite genes resulted in enhanced production of known cytosporones B (1, 360%), C (2, 580%) and E (3, 890%), as well as the production of the previously undescribed cytosporone R (4). Cytosporone E was the most bioactive, displaying an IC90 of 13 µM toward Plasmodium falciparum, with A549 cytotoxicity IC90 of 437 µM, representing a 90% inhibition therapeutic index (TI90 = IC90 A459/IC90 P. falciparum) of 33. In addition, cytosporone E was active against MRSA with a minimal inhibitory concentration (MIC) of 72 µM and inhibition of MRSA biofilm at roughly half that value (minimum biofilm eradication counts, MBEC90, was found to be 39 µM).

Exploring the Chemodiversity and Biological Activities of the Secondary Metabolites from the Marine Fungus Neosartorya pseudofischeri

“…These marine fungi are an important source of structurally unique and biologically active natural products. Recent studies revealed that the cryptic biosynthetic pathways of fungi can be activated and the chemical diversity of their metabolites can be maximized by alternating their cultivation parameters systematically, such as the components of the media [1,2], co-culture [3,4], feeding precursors [5,6] and the addition of enzyme inhibitors [7,8]. For example, marine fungus Chondrostereum sp., which was isolated from soft coral Sarcophyton tortuosum , grows in different culture media and can produce various novel bioactive hirsutane-type sesquiterpenoids [9,10,11,12].…”

Multicomponent Analysis of the Differential Induction of Secondary Metabolite Profiles in Fungal Endophytes

“…According to previous reports [10,15], all epigenetic modifiers were tested at 100 µM as the standard concentration in the study. After 14 days of fermentation, ensuring the generation of enough biomass in the control conditions, submerged culture differences in morphology and SMs profiles were analyzed visually and by UHPLC-UV at 210 nm.…”

“…The majority of these epigenetic studies report the effect of using hydroxamic-acid compounds, such as SAHA (8), with similar HDAC inhibitory effects; e.g.,: the production of a new fungal biosynthetic cyclodepsipeptide (EMG-556) by Microascus sp. when cultured with SAHA [9], the production of new anti-infective cytosporones by the marine fungus Leucostoma persoonii [10] or, the biosynthesis of novel fusaric acid derivatives by the Datura stramonium endophyte when SBHA was added to its production medium [11].…”

Endophytes as in vitro production platforms of high value plant secondary metabolites

“…• 5-Butyl-6-oxo-1,6-dihydropyridine-2-carboxylic acid • 5-(But-9-enyl)-6-oxo-1,6-dihydropyridine-2-carboxylic acid Chen et al (2013) Sodium butyrate (HDAC inhibitor) Leucostoma persoonii • Novel compound -cytosporone R • Enhanced production of known cytosporones B (360%), C (580%) and E (890%) Beau et al (2012) 5-Azacytidine (DNMT inhibitor) and/or suberoylanilide hydroxamic acid (HDAC inhibitor)…”