Cryptic Aspergillus nidulans Antimicrobials

ABSTRACT Secondary metabolite (SM) production by fungi is hypothesized to provide some fitness attribute for the producing organisms. However, most SM clusters are “silent” when fungi are grown in traditional laboratory settings, and it is difficult to ascertain any function or activity of these SM cluster products. Recently, the creation of a chromatin remodeling mutant in Aspergillus nidulans induced activation of several cryptic SM gene clusters. Systematic testing of nine purified metabolites from this mutant identified an emodin derivate with efficacy against both human fungal pathogens (inhibiting both spore germination and hyphal growth) and several bacteria. The ability of catalase to diminish this antimicrobial activity implicates reactive oxygen species generation, specifically, the generation of hydrogen peroxide, as the mechanism of emodin hydroxyl activity.

[1]  Clinical,et al.  Reference method for broth dilution antifungal susceptibility testing of yeasts : Approved standard , 2008 .

[2]  Clay C C Wang,et al.  Molecular genetic analysis of the orsellinic acid/F9775 gene cluster of Aspergillus nidulans. , 2010, Molecular bioSystems.

[3]  R. Cichewicz,et al.  Epigenome manipulation as a pathway to new natural product scaffolds and their congeners. , 2010, Natural product reports.

[4]  X. Tu,et al.  Emodin-mediated protection from acute myocardial infarction via inhibition of inflammation and apoptosis in local ischemic myocardium. , 2007, Life sciences.

[5]  J. Chang,et al.  Immunosuppressive effect of emodin, a free radical generator. , 1992, European journal of pharmacology.

[6]  Corinna Lange,et al.  Genomics-driven discovery of PKS-NRPS hybrid metabolites from Aspergillus nidulans. , 2007, Nature chemical biology.

[7]  J. Vederas,et al.  [Drug discovery and natural products: end of era or an endless frontier?]. , 2011, Biomeditsinskaia khimiia.

[8]  D. Sanglard,et al.  Azole and fungicide resistance in clinical and environmental Aspergillus fumigatus isolates. , 2005, Medical mycology.

[9]  E. Bruck,et al.  National Committee for Clinical Laboratory Standards. , 1980, Pediatrics.

[10]  Clay C C Wang,et al.  Characterization of the Aspergillus nidulans Monodictyphenone Gene Cluster , 2010, Applied and Environmental Microbiology.

[11]  Clay C C Wang,et al.  Unlocking Fungal Cryptic Natural Products , 2009, Natural product communications.

[12]  P. W. Brian,et al.  Gliotoxin, a fungistatic metabolic product of Trichoderma viride. , 1945, The Annals of applied biology.

[13]  A. Brakhage,et al.  Activation of fungal silent gene clusters: a new avenue to drug discovery. , 2008, Progress in drug research. Fortschritte der Arzneimittelforschung. Progres des recherches pharmaceutiques.

[14]  A. Brakhage,et al.  Transannular disulfide formation in gliotoxin biosynthesis and its role in self-resistance of the human pathogen Aspergillus fumigatus. , 2010, Journal of the American Chemical Society.

[15]  M. Tribus,et al.  Histone Deacetylase Activity Regulates Chemical Diversity in Aspergillus , 2007, Eukaryotic Cell.

[16]  Clay C C Wang,et al.  Identification and Characterization of the Asperthecin Gene Cluster of Aspergillus nidulans , 2008, Applied and Environmental Microbiology.

[17]  Yoshiyuki Sakaki,et al.  Genome sequence of an industrial microorganism Streptomyces avermitilis: Deducing the ability of producing secondary metabolites , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[18]  C. R. Howell,et al.  Mechanisms in the biocontrol of Rhizoctonia solani-induced cotton seedling disease by Gliocladium virens: antibiosis. , 1995 .

[19]  Nancy P Keller,et al.  Genomic mining for Aspergillus natural products. , 2006, Chemistry & biology.

[20]  J. Frisvad,et al.  Effect of competition on the production and activity of secondary metabolites in Aspergillus species. , 2009, Medical mycology.

[21]  C. Hertweck,et al.  Discovery of aspoquinolones A-D, prenylated quinoline-2-one alkaloids from Aspergillus nidulans, motivated by genome mining. , 2006, Organic & biomolecular chemistry.

[22]  D. Ratkowsky,et al.  Antibacterial metabolites from Australian macrofungi from the genus Cortinarius. , 2010, Phytochemistry.

[23]  T. Nakayama,et al.  Generation of free radical and hydrogen peroxide from 2-hydroxyemodin, a direct-acting mutagen, and DNA strand breaks by active oxygen. , 1987, Toxicology letters.

[24]  Gary W. Jones,et al.  Self-Protection against Gliotoxin—A Component of the Gliotoxin Biosynthetic Cluster, GliT, Completely Protects Aspergillus fumigatus Against Exogenous Gliotoxin , 2010, PLoS pathogens.

[25]  Y. Reyes-Domínguez,et al.  Chromatin-level regulation of biosynthetic gene clusters. , 2009, Nature chemical biology.

[26]  C. Jin,et al.  Microcalorimetric assay on the antimicrobial property of five hydroxyanthraquinone derivatives in rhubarb (Rheum palmatum L.) to Bifidobacterium adolescentis. , 2010, Phytomedicine : international journal of phytotherapy and phytopharmacology.

[27]  F. Kempken,et al.  Secondary chemicals protect mould from fungivory , 2007, Biology Letters.

[28]  B. Barrell,et al.  Complete genome sequence of the model actinomycete Streptomyces coelicolor A3(2) , 2002, Nature.

[29]  William H. Majoros,et al.  Genomic sequence of the pathogenic and allergenic filamentous fungus Aspergillus fumigatus , 2005, Nature.

[30]  M. Lorito,et al.  Synergistic interaction between fungal cell wall degrading enzymes and different antifungal compounds enhances inhibition of spore germination. , 1994, Microbiology.

[31]  Wen-Yueh Ho,et al.  Molecular genetic mining of the Aspergillus secondary metabolome: discovery of the emericellamide biosynthetic pathway. , 2008, Chemistry & biology.

[32]  N. Keller,et al.  Pathogenesis of Aspergillus fumigatus in Invasive Aspergillosis , 2009, Clinical Microbiology Reviews.

[33]  R. Larkin,et al.  Efficacy of Various Fungal and Bacterial Biocontrol Organisms for Control of Fusarium Wilt of Tomato. , 1998, Plant disease.

[34]  Wolfgang Schmidt-Heck,et al.  Intimate bacterial–fungal interaction triggers biosynthesis of archetypal polyketides in Aspergillus nidulans , 2009, Proceedings of the National Academy of Sciences.

[35]  J. S. Choi,et al.  Comparative evaluation of antioxidant potential of alaternin (2-hydroxyemodin) and emodin. , 2000, Journal of agricultural and food chemistry.

[36]  A. Davidson,et al.  A gene cluster containing two fungal polyketide synthases encodes the biosynthetic pathway for a polyketide, asperfuranone, in Aspergillus nidulans. , 2009, Journal of the American Chemical Society.