A polyketide synthase-peptide synthetase gene cluster from an uncultured bacterial symbiont of <i>Paederus</i> beetles

TLDR

Drug candidates from marine and terrestrial invertebrates, such as the antitumor pederin polyketides from beetles and sponges, are often derived from uncultured bacterial symbionts, but their development is limited by low yields and challenges in sustaining invertebrate cultures. The study aimed to identify the true producer of pederin and explore alternative sources by cloning its biosynthetic genes from Paederus fuscipes beetles. The authors cloned the putative pederin biosynthesis gene cluster from total DNA of Paederus fuscipes beetles. Sequence analysis revealed a 54‑kb ped cluster with bacterial‑like architecture encoding a mixed PKS/NRPS system lacking internal AT domains but flanked by monodomain AT genes, present only in high‑pederin beetles, and its upstream region mirrors pederin structure, indicating evolutionary links between beetle and sponge pederin pathways.

Abstract

Many drug candidates from marine and terrestrial invertebrates are suspected metabolites of uncultured bacterial symbionts. The antitumor polyketides of the pederin family, isolated from beetles and sponges, are an example. Drug development from such sources is commonly hampered by low yields and the difficulty of sustaining invertebrate cultures. To obtain insight into the true producer and find alternative supplies of these rare drug candidates, the putative pederin biosynthesis genes were cloned from total DNA of Paederus fuscipes beetles, which use this compound for chemical defense. Sequence analysis of the gene cluster and adjacent regions revealed the presence of ORFs with typical bacterial architecture and homologies. The ped cluster, which is present only in beetle specimens with high pederin content, is located on a 54-kb region bordered by transposase pseudogenes and encodes a mixed modular polyketide synthase/nonribosomal peptide synthetase. Notably, none of the modules contains regions with homology to acyltransferase domains, but two copies of isolated monodomain acyltransferase genes were found at the upstream end of the cluster. In line with an involvement in pederin biosynthesis, the upstream cluster region perfectly mirrors pederin structure. The unexpected presence of additional polyketide synthase/nonribosomal peptide synthetase modules reveals surprising insights into the evolutionary relationship between pederin-type pathways in beetles and sponges.