Isolation of Human Cancer Cell Growth Inhibitory, Antimicrobial Lateritin from a Mixed Fungal Culture

Abstract

The purpose of this study was to attempt the reproducible coculture of more than two fungi for biosynthesis of potential antineoplastic substances. Five different fungi were simultaneously inoculated into broth cultures and grown for two weeks. Cancer cell line bioassay-guided fractionation, NMR, and mass spectroscopy led to the isolation and characterization of lateritin. Lateritin inhibited the growth of a mini-panel of human cancer cell lines, gram-positive bacteria, and Candida albicans. Individually, the five fungi did not synthesize detectable levels of lateritin. This study adds to the small but growing body of evidence that mixed fermentation is a viable avenue for natural product drug discovery. In addition, this is the first report of the reproducible coculture of more than two microbes for natural product biosynthesis, and the first report of the human solid tumor cell line and antimicrobial activities of lateritin.

Key words

coculture - mixed fermentation - lateritin - natural product - anticancer agent

References

• 1 Pettit R K. Mixed fermentation for natural product drug discovery.  Appl Microbiol Biotechnol. 2009;  83 19-25
• 2 Hasumi K H, Shinohara C, Iwanaga T, Endo A. Lateritin, a new inhibitor of acyl-coA: cholesterol acyltransferase produced by Gibberella lateritium IFO 7188.  J Antibiot. 1993;  46 1782-1787
• 3 Oh H, Taewan K, Oh G S, Pae H O, Hong K H, Chai K Y, Kwon T O, Chung H T, Lee H S. (3R,6R)-4-methyl-6-(1-methylethyl)-3-phenylmethyl-perhydro-1,4-oxazine-2,5-dione: an apoptosis-inducer from the fruiting bodies of Isaria japonica.  Planta Med. 2002;  68 345-348
• 4 Cody W L, He J X, Reily M D, Haleen S J, Walker D M, Reyner E L, Stewart B H, Doherty A M. Design of a potent combined pseudopeptide endothelin-A/endothelin B receptor antagonist, Ac-DBhg¹⁶-Leu-Asp-Ile-[NMe]Ile-Trp²¹ (PD 156252): examination of its pharmacokinetic and spectral properties.  J Med Chem. 1997;  40 2228-2240
• 5 Fairlie D P, Abbenante G, March D R. Macrocyclic peptidomimetics- forcing peptides into bioactive conformations.  Curr Med Chem. 1995;  2 654-686
• 6 Haviv F, Fitzpatrick T D, Swenson R E, Nichols C J, Mort N A, Bush E N, Diaz G, Bammert G, Nguyen A, Rhutasel N S, Nellans H N, Hoffman D J. Effect of N-methyl substitution of the peptide bonds in luteinizing hormone-releasing hormone agonists.  J Med Chem. 1993;  36 363-369
• 7 Türker R K, Hall M M, Yamamoto M, Sweet C S, Bumpus F M. A new, long-lasting competitive inhibitor of angiotensin.  Science. 1972;  177 1203-1205
• 8 Hughes A B, Sleebs M M. Total synthesis of bassiatin and its stereoisomers: novel divergent behavior of substrates in Mitsunobu cyclizations.  J Org Chem. 2005;  70 3079-3088
• 9 Kagamizono T, Nishino E, Matsumoto K, Kawashima A, Kishimoto M, Sakai N, He B M, Chen Z X, Adachi T, Morimoto S, Hanada K. Bassiatin, a new platelet aggregation inhibitor produced by Beauveria bassiana K-717.  J Antibiot. 1995;  48 1407-1412
• 10 Suffness M, Douros J. Approach to acquisition of new anticancer drugs. Drugs of plant origin.  Methods Cancer Res. 1979;  16 73-126
• 11 Monks A, Scudiero D, Skehan P, Shoemaker R, Paull K, Vistica D, Hose C, Langley J, Cronise P, Vaigro-Wolff A, Gray-Goodrich M, Campbell H, Mayo J, Boyd M. Feasibility of a high-flux anticancer drug screen using a diverse panel of cultured human tumor cell lines.  J Natl Cancer Inst. 1991;  83 757-766
• 12 National Committee for Clinical Laboratory Standards .Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically: approved standard M7-A4. Wayne; NCCLS 1997
• 13 National Committee for Clinical Laboratory Standards .Reference method for broth dilution antifungal susceptibility testing of yeasts: approved standard M27-A. Wayne; NCCLS 1997