Genomic seuqences for the discovery of compounds

Microbial secondary metabolites are an important source of new drugs. In the marine ecosystem the actinomycetes are an important source of a large range of antibiotics, in particular the Streptomyces. However the number of newly found compounds has decreased over recent years and Zang et al (2012) suggest a new approach to screen systems for possible sources of useful products. By examining the genomic sequences of isolates genetic clusters may be discovered which may encode for undiscovered metabolites. With Streptomyces encoding for many antibiotics the authors analysed the genetic sequence of a newly discovered strain Streptomyces sp. W007 to determine the possible application of secondary metabolites for medical use.

Samples were isolated from seawater and genomic DNA was extracted and analysed. In addition a crude extract was made from isolated cultures. Using chromatography seven different fractions. These fractions were then further purified and resulted in six separate compounds which three were used to determine cytotoxicity. Cytotoxicity assays were preformed on human cancer cell lines of lung cancer A549, gastric cancer BGC-823 and breast cancer MCF7. The cancer cells were seeded into 96well plates and treated with the specific isolated compounds at concentration of 0.1, 1 and 10 µM over a period of 72 hours. Additional antifungal tests were performed on five different species of fungi associated with agricultural fungal diseases using the crude extract.

Initial antifungal activity of the extract from Streptomyces sp. W007 resulted in a significant decrease in fungal growth compared to control groups. This indicates that secondary metabolites produced by this bacterium could quite possibly be used in agricultural fungal disease control. Analysis of the genetic structure of Streptomyces  sp. W007 would imply that it has the potential to produce angucyclinone antibiotic analogs, and based on sequence data several novel antibiotics may have been isolated from the crude extract made from the isolated cultures. Isolated compounds 2,5 and 6 were used for cytotoxicity testing. Results indicated that compound 2 provided a strong selective inhibition of 71.8% on lung cancer cells at 10µM, but provided no inhibition for both the gastric and breast cancer cells. Compound 5 provided a weak inhibition to gastic cancer cells at a maximum of 29% at 10µM, and provided no inhibition to the other two cancers. Compound 6 provided a moderate inhibition to gastric cancer (48%) at 1µM, and an additional weak inhibition to lung cancer. The authors suggest that both compound 2 and 6 may have potential use in the treatment of cancer, with compound 5 possibly not being effective enough.

Overall the authors suggest that the scanning of genomic DNA for gene clusters that may encode for antibiotics may prove to be fruitful and many novel antibiotics may be found in this way. Using this method they have found that the newly discovered Streptomyces sp. W007 produces two novel antibiotics of the angucyclinone family in addition to other compounds. 

Zang, H., Wang, H., Wang, Y., Cui, Y., Xie, Z., Pu, Y., Pei, S., Li, F., Qin, S. (2012). Genomic sequence-based discovery of novel angucyclinone antibiotics from marine Streptomyces sp. W007. FEMS Microbial Letters. 332, 105-112.