Genomics-driven discovery of PKS-NRPS hybrid metabolites from Aspergillus nidulans

Abstract

In the postgenomic era it has become increasingly apparent that the vast number of predicted biosynthesis genes of microorganisms is not reflected by the metabolic profile observed under standard fermentation conditions. In the absence of a particular (in most cases unknown) trigger these gene loci remain silent. Because these cryptic gene clusters may code for the biosynthesis of important virulence factors, toxins, or even drug candidates, new strategies for their activation are urgently needed to make use of this largely untapped reservoir of potentially bioactive compounds. The discovery of new microbial metabolites through genome mining has proven to be a very promising approach. Even so, the investigation of silent gene clusters is still a substantial challenge, particularly in fungi. Here we report a new strategy for the successful induction of a silent metabolic pathway in the important model organism Aspergillus nidulans, which led to the discovery of novel PKS-NRPS hybrid metabolites.

Bacteria-induced natural product formation in the fungus Aspergillus nidulans requires Saga/Ada-mediated histone acetylation

“…Recent data further complicate a serious estimation because communication occurs between gene clusters, which could potentially lead to even more compounds (5). A major hurdle to identifying this untapped reservoir, however, is the observation that most of these gene clusters are silent under standard laboratory conditions (6)(7)(8). To address this problem, methods were established to activate silent gene clusters by genetic engineering (6,7,9).…”

“…A major hurdle to identifying this untapped reservoir, however, is the observation that most of these gene clusters are silent under standard laboratory conditions (6)(7)(8). To address this problem, methods were established to activate silent gene clusters by genetic engineering (6,7,9). The most challenging question, however, is the identification of the true function of these compounds in the habitat.…”

Functionally Optimized Neuritogenic Farinosone C Analogs: SAR-Study and Investigations on Their Mode of Action

“…9,10,21−23 While the biosynthesis of these compounds is likely to be related, 24,25 their synthesis required at least 14 steps. 22 From a very limited structure−activity relationship study (SAR), we learned that the much simpler L-tyrosinol-propionamide 4 was able to induce neuronal differentiation, albeit at higher concentration than the parent analog 3.…”

Aspernidine A and B, prenylated isoindolinone alkaloids from the model fungus Aspergillus nidulans

“…To gain access to this untapped reservoir of potentially bioactive natural products, various strategies to induce the expression of silent genes have been developed. 4,7 Important recent examples involve the ectopic expression of a regulatory gene, 8 the induction of a transcription activator by promotor exchange, 9 as well as modulation of the epigenetic regulation of biosynthetic genes at the chromatin level. [10][11][12][13] Furthermore, it was shown that the intimate contact between A. nidulans and a soil-dwelling actinomycete may lead to the specific induction of a cryptic polyketide gene cluster.…”