The Stierle Research Lab is dedicated to the isolation and structural characterization of compounds with selective biological activity from microbes isolated from unusual ecological niches.  We are currently studying the microbial population of an acid mine waste lake in Butte, Montana.  We have isolated over 50 microbes from different depth profiles of this metal-rich, acidic environment.  Each microbe is grown under varying physicochemical conditions and the resulting microbial ferment is partitioned between an aqueous and organic extract.  The potential biological activities of these extracts are determined using a series of bioassays. Signal transduction enzyme inhibition assays have been developed to target activity against specific disease conditions.  Using inhibition of these enzymes as fractionation guides, We have isolated and elucidated several novel molecules that have shown potent, selective activity against specific cancers – ovarian, non-small lung and leukemia -- in the NIH 60 human cell-line assay. 

We are also interested in targeting the antibiotic potential of these metabolites.  We use a series of standard disk assays to guide the isolation of compounds with antifungal and antibacterial activity.  The rising incidence of immunocompromised individuals has generated an array of emerging infectious diseases in critical need of prophylaxis.  Of particular interest are those compounds with antifungal activity, as opportunistic mycoses are a growing problem in immunocompromised individuals, including AIDS patients and patients on immunosuppressive therapy.  We are also collaborating with Dr. Allen Harmsen at Montana State University in the search for compounds with specific activity against Pneumocystis jirnoveci (formerly carinii).  This unusual microbe was formerly classified as a protozoan but is now classified as a fungus. It is the causative agent of Pneumocystis carinii pneumonia, an insidious opportunistic infection in immunocompromised patients. 

The Stierle lab is also looking at the potential of the Berkeley Pit Lake microbes to participate in the remediation of this 40 billion gallon acid mine waste lake that graces the northeast corner of Butte, Montana.  These efforts have led to the isolation of an unusual yeast that sorbs metals even at pH 2.3. 

The Stierle lab has long studied endosymbiotic microbes isolated from marine sponges and the inner bark of trees – notably the Northwest Pacific yew tree.  The Stierles found that many compounds reported from sponge extracts might actually have been produced by their microbial symbionts.  This work led to the discovery of a unique compound from a Bermudian sponge endosymbiotic bacterium that showed activity against both pathogenic bacteria and the AIDS virus.  The Stierles will work with collaborators at UM to determine how this compound affects the AIDS virus.

In the early 90’s The Stierles also searched for a fungal source of the drug taxol (paclitaxel), an anticancer agent which showed promise in clinical trials against refractory breast and ovarian cancers.  Unfortunately the source organism of taxol, the northwest Pacific yew tree, had been clear-cut to the point of endangerment and could not supply the growing demands for taxol.  It was clear that additional sources of taxol were necessary. Andrea isolated over 300 fungi from the inner bark and needles of yew trees in Montana, Washington, Idaho and Oregon.   In 1993, the team  published a report of a fungus isolated from the bark of the Pacific yew tree, Taxus brevifolia Nutt, which could produce taxol in de novo fashion.  This unique fungus – Taxomyces andreanae - was named after Andrea, its discoverer.  The Stierles hope to compare the production of taxol by the tree and the fungus.

D. Stierle and A. Stierle.  2010. Three New Berkeleyones From a Deep Water Acid Mine Waste Fungus.  Manuscript in preparation.  

A. A. Stierle, D. B. Stierle, B. Patacini,  2009. The Berkeleyamides: Four New Amides From Penicillium rubrum, a Deep Water Acid Mine Waste Fungus. J. Nat. Prod.71(5), 856-860.

Stierle, D. B.; Stierle, A. A.; Patacini, B.  2007.  The Berkeleyacetals, Three Meroterpenes from a Deep Water Acid Mine Waste Penicillium.  J. Nat. Prod. 70(11); 1820-1823.

A. Stierle, D. Stierle, and K. Kelley, 2006.  Berkelic Acid,  A Novel Spiroketal with Highly Specific Anti-tumor Activity from an Acid-Mine Waste Fungal Extremophile.  J. Org. Chem. 71: 5357-5360.

A. Stierle, D.Stierle, and K.Kemp,  2004.  Novel Sesquiterpenoid Matrix Metalloproteinase-3 Inhibitors from an Acid Mine Waste Extremophile.  in August 2004 D.John Faulkner and Paul Scheurer memorial issue of J.Nat. Prod. 67(8): 1392-1395.

D.Stierle, A. Stierle, J.David Hobbs, Janalee Stokken, and J. Clardy. 2004. Berkeleydione and Berkeleytrione, NewBioactive Metabolites from an Acid Mine Organism.  Organic Letters 6(6): 1049-1052.

Andrea A. Stierle, Donald B. Stierle, Keith Parker, Eric Goldstein, Tim Bugni, Chad Baarson, Julie Gress, Danielle Blake. 2003.  A Novel 5-HT Receptor Ligand and Related Cytotoxic Compounds from an Acid Mine Waste Extremophile. J.Nat.Prod., 66: 1097-1100.

Donald B. Stierle, Andrea Stierle, Timothy Bugni. 2003.  Sequoiamonascins: novel antitumor metabolites of the redwood endophyte, Aspergillus parasiticus.   J.Org. Chem.  68: 4966-4967

A. Stierle, D. Stierle, T. Bugni . 2001.  Sequoiatones C-F, constituents of the redwood endophyte, Aspergillus parasiticus.   J. Nat. Prod.  64: 1350-1353.

Andrea A. Stierle and Donald B. Stierle.  Bioactive compounds from four          endophytic Penicillium sp. isolated from the northwest Pacific yew tree.  In:   “Bioactive Natural     Products”, Atta-Ur-Rahman, Ed.; Elsevier Science Publishers: Amsterdam. Vol. 24. 2000 pp 933-978.