Epigenetic tailoring for the production of anti-infective cytosporones from the marine fungus Leucostoma persoonii.
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).
Department of Chemistry and Center for Molecular Diversity in Drug Design, Discovery and Delivery, University of South Florida, Tampa, FL 33620, USA.
Jeremy
J
Beau
Department of Chemistry and Center for Molecular Diversity in Drug Design, Discovery and Delivery, University of South Florida, Tampa, FL 33620, USA.
Nida
N
Mahid
Department of Cell Biology, Microbiology and Molecular Biology, University of South Florida, Tampa, FL 33620, USA.
Whittney N
WN
Burda
Department of Cell Biology, Microbiology and Molecular Biology, University of South Florida, Tampa, FL 33620, USA.
Lacey
L
Harrington
Department of Cell Biology, Microbiology and Molecular Biology, University of South Florida, Tampa, FL 33620, USA.
Lindsey N
LN
Shaw
Department of Global Health, University of South Florida, Tampa, FL 33620, USA.
Tina
T
Mutka
Department of Global Health, University of South Florida, Tampa, FL 33620, USA.
Dennis E
DE
Kyle
Department of Global Health, University of South Florida, Tampa, FL 33620, USA.
Betty
B
Barisic
Department of Global Health, University of South Florida, Tampa, FL 33620, USA.
Alberto
A
Van Olphen
Department of Chemistry and Center for Molecular Diversity in Drug Design, Discovery and Delivery, University of South Florida, Tampa, FL 33620, USA.
Bill J
0000-0003-3033-5779
BJ
Baker
D000890:Anti-Infective Agents / Q000302:isolation & purification / Q000378:metabolism* / Q000494:pharmacology; D059001:Aquatic Organisms / Q000235:genetics / Q000302:isolation & purification* / Q000378:metabolism*; D001572:Benzofurans / Q000302:isolation & purification / Q000378:metabolism* / Q000494:pharmacology; D018441:Biofilms / Q000187:drug effects; D001688:Biological Products / Q000302:isolation & purification / Q000494:pharmacology; D002460:Cell Line; D057890:Epigenomics / Q000379:methods; D005658:Fungi / Q000737:chemistry* / Q000235:genetics / Q000302:isolation & purification / Q000378:metabolism*; D006801:Humans; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects; D008826:Microbial Sensitivity Tests; D010648:Phenylacetates / Q000302:isolation & purification / Q000378:metabolism* / Q000494:pharmacology
D000890:Anti-Infective Agents; D001572:Benzofurans; D001688:Biological Products; D010648:Phenylacetates; C531461:cytosporone B; C492581:cytosporone E