Genome mining and activation of silent fungal gene clusters by microbial communication: A new avenue to drug discovery

Low-molecular-weight natural products are important for intercellular communication. In addition, many of these compounds have found applications in medicine for instance as antibiotics. Genome mining efforts indicate that the capability of fungi to produce secondary metabolites has been substantially underestimated. Many of their biosynthesis gene clusters are silent under standard cultivation conditions (1). By genetic engineering, we could activate such silent gene clusters, which led to the production of novel compounds (2,3). Furthermore, we have discovered that communication between microorganisms represents a physiological trigger for activation of such silent fungal gene clusters (4). The physical interaction of the fungus Aspergillus nidulans with the soil-dwelling bacterium Streptomyces rapamycinicus, led to the selective activation of the silent polyketide synthase gene cluster encoding orsellinic acid biosynthesis (4). This reprogramming of the fungus by the bacterium requires the histone acetylase GcnE of A. nidulans, which is part of the Saga/Ada complex. GcnE was shown to specifically increase the K14 and K9 acetylation of histone 3 at genes belonging to the orsellinic acid biosynthesis gene clusters after co-incubation with S. rapamycinicus (5, 6). Knowledge of these regulatory interactions will pave the way to a novel avenue to drug discovery through targeted activation of silent gene clusters.

(1) Brakhage (2013) Nature Rev Microbiol; (2) Scherlach et al. (2011) Angew Chem Int Ed; (3) Macheleidt et al. (2015) Mol Microbiol; (4) Schroeckh et al. (2009) PNAS; (5) Nützmann et al. (2011) PNAS; (6) Nützmann et al. (2013) Appl Environm Microbiol