The macrocyclic trichothecenes are a class of potent antibiotics which possess a wide range of bioactivity including insecticidal, antifungal, antibacterial, and antiviral. They also are phytoxic and cytotoxic and exhibit a high degree of cytostacitity; the latter property makes them attractive antitumor candidates. The cytotoxicity of a series of trichothecenes, which includes both simple (e.g. T-2 toxin, anguidine, verrucarol, etc.) and macrocyclic trichothecenes, has been shown to correlate strongly and inversely with the rates of acid-catalyzed rearrangements to the nontoxic apotrichothecenes. A model to explain the structure-activity relationship for the chemical reactivity is proposed and a series of trichothecene derivatives, some having rigid conformations, are to be prepared and their chemical and biological activities are to be measured. In a collaborative study, metabolism studies in dogs are to be conducted on verrucarol, a relatively weakly toxic trichothecene, which will evaluate the relevance of the trichothecene with apotrichothecene reaction to the in vivo metabolism. A series of chemical modifications are to be carried out with a new class of highly toxic macrocyclic trichothecenes, the myrotoxins, which, based on our previous models, will yield highly active in vivo anticancer agents of high potency. In related work, we are collaborating with scientists at the Center for Disease Control (CDC) in Atlanta, GA and with workers at NIOSH in Morgantown, WV in the evaluation of the role played by toxigenic isolates of Stachybotrys atra in the etiology of legionnaire's disease (CDC) and indoor air pollution (NIOSH). Recent evidence suggests that this organism, in certain circumstances, may be a source of some health problems for people living or working in buildings contaminated with this fungus.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM043724-14
Application #
2182148
Study Section
Bacteriology and Mycology Subcommittee 2 (BM)
Project Start
1979-07-01
Project End
1995-12-31
Budget Start
1994-01-01
Budget End
1995-12-31
Support Year
14
Fiscal Year
1994
Total Cost
Indirect Cost
Name
University of Maryland College Park
Department
Chemistry
Type
Schools of Earth Sciences/Natur
DUNS #
City
College Park
State
MD
Country
United States
Zip Code
20742
Jarvis, B B; Wang, S (1999) Stereochemistry of the roridins. Diastereomers of roridin E. J Nat Prod 62:1284-9
Trapp, S C; Hohn, T M; McCormick, S et al. (1998) Characterization of the gene cluster for biosynthesis of macrocyclic trichothecenes in Myrothecium roridum. Mol Gen Genet 257:421-32
Hodgson, M J; Morey, P; Leung, W Y et al. (1998) Building-associated pulmonary disease from exposure to Stachybotrys chartarum and Aspergillus versicolor. J Occup Environ Med 40:241-9
Jarvis, B B; Wang, S; Cox, C et al. (1996) Brazilian Baccharis toxins: livestock poisoning and the isolation of macrocyclic trichothecene glucosides. Nat Toxins 4:58-71
Jarvis, B B; Zhou, Y; Jiang, J et al. (1996) Toxigenic molds in water-damaged buildings: dechlorogriseofulvins from Memnoniella echinata. J Nat Prod 59:553-4
Jarvis, B B; Wang, S; Ammon, H L (1996) Trichoverroid stereoisomers. J Nat Prod 59:254-61
Jarvis, B B; Salemme, J; Morais, A (1995) Stachybotrys toxins. 1. Nat Toxins 3:10-6
Coon, S L; Kotob, S; Jarvis, B B et al. (1994) Homogentisic acid is the product of MelA, which mediates melanogenesis in the marine bacterium Shewanella colwelliana D. Appl Environ Microbiol 60:3006-10
Jarvis, B B; DeSilva, T; McAlpine, J B et al. (1992) New trichoverroids from Myrothecium verrucaria isolated by high speed countercurrent chromatography. J Nat Prod 55:1441-6
Bean, G A; Jarvis, B B; Aboul-Nasr, M B (1992) A biological assay for the detection of Myrothecium spp. produced macrocyclic trichothecenes. Mycopathologia 119:175-80

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