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. 2012 Apr;10(4):762-774.
doi: 10.3390/md10040762. Epub 2012 Mar 28.

Epigenetic tailoring for the production of anti-infective cytosporones from the marine fungus Leucostoma persoonii

Jeremy Beau  1 , Nida Mahid  1 , Whittney N Burda  2 , Lacey Harrington  2 , Lindsey N Shaw  2 , Tina Mutka  3 , Dennis E Kyle  3 , Betty Barisic  3 , Alberto Van Olphen  3 , Bill J Baker  1
Affiliations

Epigenetic tailoring for the production of anti-infective cytosporones from the marine fungus Leucostoma persoonii

Jeremy Beau et al. Mar Drugs. 2012 Apr.

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 IC(90) of 13 µM toward Plasmodium falciparum, with A549 cytotoxicity IC(90) of 437 µM, representing a 90% inhibition therapeutic index (TI(90) = IC(90) A459/IC(90)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).

Keywords: MRSA; epigenetics; fungus; malaria; mangrove.

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Figures

Figure 1
Figure 1
Structures of the cytosporones (1–4).
Figure 2
Figure 2
(A) Average of triplicate zone of inhibition (ZOI) determinations against MRSA for the crude methanol extract at each concentration of epigenetic modifier; (B) Average of triplicate ZOI determinations against MRSA for the crude extract at each time point of incubation. The sterile disks measure 6 mm, thus a result of 6 mm indicates no inhibition at that concentration.
Figure 3
Figure 3
Overlay of LC/MS total ion chromatograms (TIC) from each concentration of crude extracts of DNA methyltransferase (DNMT)-inhibited cultures. Region highlighted indicates varying levels of the peaks of interest.
Figure 4
Figure 4
Key HMBC correlations leading to the identification of cytosporone R (4).
See this image and copyright information in PMC

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