Monday, August 12, 2013
Pavilion (Sheraton San Diego)
Genomics-guided natural product discovery is effective and particularly suitable for small research laboratories with very limited resources. Mining the genome of Burkholderia thailandensis E264 revealed a hybrid nonribosomal peptide synthetase-polyketide synthase (NRPS–PKS) biosynthetic gene cluster that resembles that of FK228 (romidepsin, Istodax), 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 FK228, which led us not only to discover a new FK228 analogue that possesses 10-fold more potent antiproliferative activities than that of FK228, but also to find out that this Burkholderia strain produces nearly 100 times more FK228 than Chromobacterium violaceum No. 968, the original FK228 producer. Another hybrid PKS–NRPS gene cluster is 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 thailandepsins or thailanstatins are under intensive investigations as potential anticancer lead compounds, and preliminary results are very promising. Collectively, B. thailandensis species have proven to be a very good source of potent natural products useful as lead compounds for the development of next generation of anticancer drugs.