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1.  Genomic and Metabolomic Insights into the Natural Product Biosynthetic Diversity of a Feral-Hog-Associated Brevibacillus laterosporus Strain 
PLoS ONE  2014;9(3):e90124.
Bacteria associated with mammals are a rich source of microbial biodiversity; however, little is known concerning the abilities of these microbes to generate secondary metabolites. This report focuses on a bacterium isolated from the ear of a feral hog from southwestern Oklahoma, USA. The bacterium was identified as a new strain (PE36) of Brevibacillus latersporus, which was shown via genomic analysis to contain a large number of gene clusters presumably involved in secondary metabolite biosynthesis. A scale-up culture of B. latersporus PE36 yielded three bioactive compounds that inhibited the growth of methicillin-resistant Staphylococcus aureus (basiliskamides A and B and 12-methyltetradecanoic acid). Further studies of the isolate's secondary metabolome provided both new (auripyrazine) and previously-described pyrazine-containing compounds. In addition, a new peptidic natural product (auriporcine) was purified that was determined to be composed of a polyketide unit, two L-proline residues, two D-leucine residues, one L-leucine residue, and a reduced L-phenylalanine (L-phenylalanol). An examination of the genome revealed two gene clusters that are likely responsible for generating the basiliskamides and auriporcine. These combined genomic and chemical studies confirm that new and unusual secondary metabolites can be obtained from the bacterial associates of wild mammals.
doi:10.1371/journal.pone.0090124
PMCID: PMC3940840  PMID: 24595070
2.  Production of Cytotoxic Glidobactins/Luminmycins by Photorhabdus asymbiotica in Liquid Media and Live Crickets 
Journal of natural products  2012;75(11):2007-2011.
Photorhabdus asymbiotica engages in a two-part life cycle that requires adaptation to both symbiotic and pathogenic phases. The genome of P. asymbiotica contains several gene clusters, which are predicted to be involved in the biosynthesis of unique secondary metabolites that are hypothesized to enhance the bacterium’s pathogenic capabilities. However, recent reports on Photorhabdus secondary metabolite production have indicated that many of its genes are silent under laboratory culture conditions. Using a circumscribed panel of media and alternative fermentation conditions, we have successfully achieved the production of a series of new and known glidobactin/luminmycin derivatives from P. asymbiotica including glidobactin A (1), luminmycin A (2) and luminmycin D (3). These compounds were also obtained upon infection of live crickets with the bacterium. Luminmycin D showed cytotoxicity against human pancreatic cells (IC50 of 0.11 µM), as well as proteasome inhibition (IC50 of 0.38 µM).
doi:10.1021/np300623x
PMCID: PMC3570697  PMID: 23095088
3.  A Diarylcyclopentendione Metabolite Obtained from a Preussia typharum Isolate Procured Using an Unconventional Cultivation Approach 
Journal of natural products  2012;75(10):1819-1823.
An uncommon 2,5-diarylcyclopenteneone compound preussidone (1) and a new biphenyl compound 1',5-dimethoxy-3,5'-dimethyl-2,3'-oxybiphenyl-1,2'-diol (4), together with two known biphenyl compounds 5-methoxy-3,5'-dimethyl-2,3'-oxybiphenyl-1,1',2'-triol (2) and cyperin (3) were obtained from a Preussia typharum isolate that was procured using a panel of unconventional media formulations. The structures of the new compounds were established by NMR and mass spectrometry, while the absolute configuration of 1 was assigned by quantum chemical ECD and VCD calculations. The antimicrobial and DPPH radical scavenging activities of 1-4 were tested. Compounds 2 and 4 exhibited DPPH radical scavenging activities that were comparable to the positive control ascorbic acid.
doi:10.1021/np300473h
PMCID: PMC3483373  PMID: 23046341
4.  Secondary metabolites produced by fungi derived from a microbial mat encountered in an iron-rich natural spring 
Tetrahedron letters  2012;53(32):4202-4205.
A collection of fungal isolates was obtained from a complex microbial mat, which occupied an iron-rich freshwater spring that feeds into Clear Creek, Golden, Colorado, USA. Two of the fungal isolates, a Glomeromycete (possible Entrophospora sp.) and a Dothideomycete (possible Phaeosphaeria sp.), were investigated for bioactive secondary metabolites. In total, six new compounds consisting of clearanols A–E (5, 6, 10–12) and disulochrin (7) were purified and their structures were determined. Disulochrin exhibited modest antibacterial activity against methicillin-resistant Staphylococcus aureus, whereas clearanol C showed weak inhibitory activity against Candida albicans biofilm formation.
doi:10.1016/j.tetlet.2012.05.156
PMCID: PMC3404852  PMID: 22844162
Biofilm; Fungi; Microbial mat; Secondary metabolites
5.  Waikialoid A Suppresses Hyphal Morphogenesis and Inhibits Biofilm Development in Pathogenic Candida albicans 
Journal of Natural Products  2012;75(4):707-715.
A chemically prolific strain of Aspergillus was isolated from a soil sample collected near Waikiki Beach, Honolulu, Hawaii. The fungus produced several secondary metabolites that were purified and placed in our natural products library, which was later screened for substances capable of inhibiting biofilm formation by Candida albicans. It was determined that one of the secondary metabolites from the Hawaiian fungal isolate, a new complex prenylated indole alkaloid named waikialoid A (1), inhibited biofilm formation with an IC50 value of 1.4 μM. Another structurally unrelated, presumably polyketide metabolite, waikialide A (15), also inhibited C. albicans biofilm formation, but was much less potent (IC50 value of 32.4 μM). Microscopy studies revealed that compound 1 also inhibited C. albicans hyphal morphogenesis. While metabolite 1 appears ineffective at disrupting preformed biofilms, the accumulated data indicate that the new compound may exert its activity against C. ablicans during the early stages of surface colonization involving cell adherence, hyphal development, and/or biofilm assembly. Unlike some other stephacidin/notoamide compounds, metabolite 1 was not cytotoxic to fungi or human cells (up to 200 μM), which makes this an intriguing model compound for studying the adjunctive use of biofilm inhibitors in combination with standard antifungal antibiotics.
doi:10.1021/np2009994
PMCID: PMC3338887  PMID: 22400916
6.  Reappraising the structures and distribution of metabolites from black aspergilli containing uncommon 2-benzyl-4H-pyran-4-one and 2-benzylpyridin-4(1H)-one systems 
Journal of natural products  2011;74(9):1959-1964.
To date, natural products containing 2-benzyl-4H-pyran-4-one and 2-benzylpyridin-4(1H)-one substructures have been encountered in relatively few fungi outside of the black aspergilli clade. While exploring the occurrence of these compounds among Aspergillus spp., it was determined that the structures of the unusual furopyrrols tensidols A and B (5 and 6) and JBIR-86 and JBIR-87 (9 and 10) were incorrect and should be reassigned as 2-benzyl-4H-pyran-4-ones (7, 8, 11e, and 12, respectively). The origin of the unique N-phenyl groups in the 2-benzylpyridin-4(1H)-ones nygerones A and B (1 and 2) was also examined and it was established that N-phenylamides added to the culture medium were suitable substrates for generating these metabolites; however, this phenomenon remained limited to a single fungus in our collection (Aspergillus niger ATCC 1015). A variety of 2-benzyl-4H-pyran-4-ones and 2-benzylpyridin-4(1H)-ones were detected among the black aspergilli, but only pestalamide B (13) was found in all eleven of the tested strains. These metabolites, as well as a group of synthetic analogues demonstrated weak antifungal activity against several Candida strains, Aspergillus flavus, and Aspergillus fumigatus.
doi:10.1021/np200454z
PMCID: PMC3179785  PMID: 21854017
7.  Association Between a Functional Variant Downstream of TNFAIP3 and Systemic Lupus Erythematosus 
Nature genetics  2011;43(3):253-258.
Systemic Lupus Erythematosus (SLE, OMIM 152700) is an autoimmune disease characterized by self-reactive antibodies resulting in systemic inflammation and organ failure. TNFAIP3, encoding the ubiquitin-modifying enzyme A20, is an established susceptibility locus for SLE. By fine mapping and genomic resequencing in ethnically diverse populations we fully characterized the TNFAIP3 risk haplotype and isolated a novel TT>A polymorphic dinucleotide associated with SLE in subjects of European (P = 1.58 × 10−8; odds ratio (OR) = 1.70) and Korean (P = 8.33 × 10−10; OR = 2.54) ancestry. This variant, located in a region of high conservation and regulatory potential, bound a nuclear protein complex comprised of NF-κB subunits with reduced avidity. Furthermore, compared with the non-risk haplotype, the haplotype carrying this variant resulted in reduced TNFAIP3 mRNA and A20 protein expression. These results establish this TT>A variant as the most likely functional polymorphism responsible for the association between TNFAIP3 and SLE.
doi:10.1038/ng.766
PMCID: PMC3103780  PMID: 21336280
8.  Chemical Epigenetics Alters the Secondary Metabolite Composition of Guttate Excreted by an Atlantic-Forest-Soil-Derived Penicillium citreonigrum 
Journal of natural products  2010;73(5):942-948.
Chemical epigenetic manipulation of Penicillium citreonigrum led to profound changes in the secondary metabolite profile of its guttate. While guttate from control cultures exhibited a relatively simple assemblage of secondary metabolites, the guttate collected from cultures treated with 50 μM 5-azacytidine (a DNA methyltransferase inhibitor) were highly enriched in compounds representing at least three distinct biosynthetic families. The metabolites obtained from the fungus included six azaphilones (sclerotiorin (1), sclerotioramine (6), ochrephilone (2), dechloroisochromophilone III (3), dechloroisochromophilone IV (4), and 6-((3E,5E)-5,7-dimethyl-2-methylenenona-3,5-dienyl)-2,4-dihydroxy-3-methylbenzaldehyde (5)), pencolide (7), and two new meroterpenes (atlantinones A and B (9 and 10, respectively)). While pencolide was detected in the exudates of both control and 5-azacytidine-treated cultures, all of the other natural products were found exclusively in the guttates of the epigenetically modified fungus. All of the metabolites from the P. citreonigrum guttate were tested for antimicrobial activity in a disk diffusion assay. Both sclerotiorin and sclerotioramine caused modest inhibition of Staphylococcus epidermidis growth; however, only sclerotioramine was active against a panel of Candida strains.
doi:10.1021/np100142h
PMCID: PMC2878378  PMID: 20450206
9.  Role of Glutathione S-Transferase Pi in Cisplatin Induced Nephrotoxicity 
SUMMARY
One of the dose-limiting toxicities of cisplatin is nephrotoxicity. Renal toxicity is localized to quiescent proximal tubule cells, where the formation of DNA-adducts cannot account for the dose-limiting toxicity. Our earlier results have shown that a glutathione-conjugate of cisplatin is metabolized to a nephrotoxicant via gamma-glutamyltranspeptidase (GGT) and a cysteine S-conjugate beta-lyase. The present study was designed to evaluate the potential role of glutathione-S-transferase Pi (GSTP) in the initial steps of the bioactivation of cisplatin. Wild-type mice and mice deficient in both murine GSTP genes (GstP1/P2) were treated with cisplatin. Toxicity in both male and female mice was evaluated 5 days after treatment and renal damage was most severe in wild-type male mice. Wild-type males have ~10-fold higher levels of GSTP expression in the liver than females, suggesting that hepatic GSTP in the wild-type males contributed to the formation of the nephrotoxic platinum-glutathione conjugate. In GstP1/P2 null mice the gender difference in toxicity was eliminated. Our data show that GSTP expression is a determinant in cisplatin-induced nephrotoxicity and its levels contribute to sex-dependent differences.
doi:10.1016/j.biopha.2008.08.004
PMCID: PMC2667699  PMID: 18819770
glutathione S-transferase Pi; cisplatin; nephrotoxicity; bone marrow toxicity; chemotherapy

Results 1-9 (9)