Caister Academic Press

Novel Antimicrobial and other Bioactive Metabolites Obtained from Silent Gene Clusters

Juan F. Martín and Paloma Liras
from: Antibiotics: Current Innovations and Future Trends (Edited by: Sergio Sánchez and Arnold L. Demain). Caister Academic Press, U.K. (2015) Pages: 275-292.

Abstract

Hundreds of secondary metabolite gene clusters have been found in the genome sequence of filamentous fungi, Streptomyces species and some rare actinomycetes (20 to 50 clusters per genome). However, the number of secondary metabolites found in the culture broths of each strain is much lower than the number of gene clusters in that particular strain. Many of the sequenced gene clusters are silent or very poorly expressed, and there is a high untapped potential for the discovery of novel antibiotics or other bioactive products. Classical strategies to trigger production of secondary metabolites rely on the use of nutritional stressing conditions such as phosphate starvation or ammonium limitation, and the addition of phosphate-precipitating or ammonium-trapping agents leads to formation of new products. Metal toxicity also triggers the production of novel secondary metabolites in some Streptomyces strains. Modification of the rpsL (for the ribosomal protein S12) or the rpoB (for the RNA polymerase β subunit) genes enhance the expression of silent or poorly expressed secondary metabolite gene clusters in several Streptomyces species. Addition of antibiotic biosynthesis "remodeling compounds" re-directs the metabolic flux to obtain new antibiotics. Modern strategies to awaken sleeping clusters include the modification of wide domain regulators that control related or even disparate pathways. Alteration of butyrolactone receptor proteins or of an oligopeptide-binding protein results also in awakening of silent gene clusters in some producer strains. Co-cultivation of Streptomyces with other bacteria or fungi, involving contact between cells, frequently triggers silent gene clusters. The potential of these strategies to trigger the expression of silent clusters in poorly studied actinobacteria other than Streptomyces, is very high.

In fungi, rearrangements of the chromatin structure by either directed mutations of some genes or by the use of "chromatin modifiers", has provided several new compounds in each of the tested fungi. Particularly, deletion or overexpression of the laeA gene that influences chromatin rearrangement, modifies the transcription of some low-expression gene clusters and awakens the expression of some silent clusters providing new compounds. Expression of the laeA gene is increased by the fungal autoinducer 1,3-diaminopropane, what may trigger some silent clusters.

Examples of new molecules synthesized by the enzyme encoded by different silent or "near-silent" gene clusters are provided in this article. Most of the novel products observed by HPLC or by bioassays still remain to be characterized chemically read more ...

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