GENOMICS-GUIDED DISCOVERY OF POTENT ANTICANCER NATURAL PRODUCTS FROM EXOTIC BACTERIAL SPECIES

Natural products are small chemical molecules produced by bacteria, fungi or plants. Natural products have made great contributions to medicine, particularly as anticancer drugs or anti-infective drugs. Currently there is a renaissance of natural product discovery due to the development of new discovery technologies and unmet medical needs. We hypothesized that exotic Gram-negative bacterial species can be a good source of diverse natural products. We analyzed the genomes of two bacterial species originally isolated from central Thailand or north Australia, and found that each genome contains multiple natural product biosynthetic gene clusters. Those information facilitated our discovery of two groups of new natural products, named thailandepsins and thailanstatins, that were found to possess potent antiproliferative activities against an array of human cancer cell lines. Additional studies are being conducted in animal models through collaborations. We thus concluded that Gram-negative bacterial species is a good source of diverse natural products, and genomics-guided discovery approach is effective and particularly suitable for small research laboratories with limited resources. Purpose (a): We hypothesize that exotic Gram-negative bacterial species can be a good source of diverse natural products. The purpose of the research is thus to discover new bioactive natural products from exotic bacterial species. Methods (b): Burkholderia thailandensis E264, a Gram-negative beta-proteobacterium strain originally isolated from a rice paddy in central Thailand, was purchased from the American Type Culture Collection (ATCC); Burkholderia thailandensis MSMB43, another Gram-negative beta-proteobacterium strain originally isolated from a water source in north Australia, was obtained from the US Centers for Disease Control (CDC). Bacterial genome analysis and natural product discovery and identification were performed according to standard procedures. Results (c): Mining the genome of B. thailandensis E264 revealed a hybrid nonribosomal peptide synthetase-polyketide synthase (NRPS–PKS) biosynthetic gene cluster that resembles that of FK228 (romidepsin, drug name Istodax) in Chromobacterium violaceum No. 968, which led us to discover thailandepsins A–F, natural analogues of FK228, and potent histone deacetylase inhibitors and antiproliferative agents with GI50 values in the sub-nM range. Mining the genome of B. thailandensis MSMB43 revealed at least 13 biosynthetic gene clusters. Among them one hybrid NRPS–PKS gene cluster is highly homologous to that of FR901464 (a prototype spliceosome inhibitor) in Pseudomonas sp. No. 2663, which led us to discover thailanstatins A–D, natural and more stable analogues of FR901464, and potent pre-mRNA splicing inhibitors and antiproliferative agents with GI50 values in the low nM range. Selected members of those natural products are under intensive collaborative investigations as anticancer drug candidates, and preliminary results are encouraging. Metabolic engineering approach is being undertaken to increase the yield of those potent compounds that are often produced in minute amounts by the wild-type bacteria. Conclusions (d): Potent new anticancer natural products have been discovered from exotic bacterial species via a genomics-guided discovery approach, which is effective and particularly suitable for small research laboratories with limited resources. We seek additional collaborations for identifying the best possible use of our small collection of potent natural products; we also seek to establish a “Texas Network for Collaborative Natural Product Discovery and Development” for sharing the resources, risks and rewards.