Genome Mining of Oxidation Modules in trans‐Acyltransferase Polyketide Synthases Reveals a Culturable Source for Lobatamides

Abstract

Bacterial trans‐acyltransferase polyketide synthases (trans‐AT PKSs) are multimodular megaenzymes that biosynthesize many bioactive natural products. They contain a remarkable range of domains and module types that introduce different substituents into growing polyketide chains. As one such modification, we recently reported Baeyer–Villiger‐type oxygen insertion into nascent polyketide backbones, thereby generating malonyl thioester intermediates. In this work, genome mining focusing on architecturally diverse oxidation modules in trans‐AT PKSs led us to the culturable plant symbiont Gynuella sunshinyii, which harbors two distinct modules in one orphan PKS. The PKS product was revealed to be lobatamide A, a potent cytotoxin previously only known from a marine tunicate. Biochemical studies show that one module generates glycolyl thioester intermediates, while the other is proposed to be involved in oxime formation. The data suggest varied roles of oxygenation modules in the biosynthesis of polyketide scaffolds and support the importance of trans‐AT PKSs in the specialized metabolism of symbiotic bacteria.

Bacterial endosymbionts protect beneficial soil fungus from nematode attack

“…Given the bacterial origin of the necroximes ( 27 ) and related benzolactones ( 25 , 28 – 30 ), we questioned the biosynthetic capability of M. verticillata and sought to identify the true producer. Since several Mortierella spp.…”

Marine natural products

“…703 Finally for ascidian chemistry, genome mining with a focus on trans-acyltransferase PKSs has identied the culturable plant symbiont Gynuella sunshinyii to be a source of the cytotoxin lobatamide A. 704 Reviews relevant to the chemistry of ascidians published in 2020 included one on ascidians with antimicrobial properties, 705 antitumour compounds from Mediterranean ascidians, 706 metabolites isolated from ascidians of the genus Didemnum 707 and the synthesis and biology of polyaromatic butenolides. 708…”

“…703 Finally for ascidian chemistry, genome mining with a focus on trans -acyltransferase PKSs has identified the culturable plant symbiont Gynuella sunshinyii to be a source of the cytotoxin lobatamide A. 704…”

Induction of antibiotic specialized metabolism by co‐culturing in a collection of phyllosphere bacteria

“…Recent studies using in silico and taxonomy‐guided approaches have revealed the diversity of BGCs or specialized metabolites in plant‐associated communities which may mediate biocontrol activities (Grubbs et al ., 2017; Blair et al ., 2018; Carrión et al ., 2019). The sampling of previously underexplored ecosystems has in turn led to the discovery of novel lipodepsipeptides and darobactin from insect microbiomes (Ganley et al ., 2018; Imai et al ., 2019), lobatamides from a plant symbiont (Ueoka et al ., 2020), or lugdunin from the human gut microbiota (Zipperer et al ., 2016). Inspired by these studies, and our own realization that specialized metabolism forms the basis of several obligate bacterial leaf symbioses (Sieber et al ., 2015; Carlier et al ., 2016; Pinto‐Carbó et al ., 2016, 2018; De Meyer et al ., 2019; Hsiao et al ., 2019), we hypothesized that the above‐ground surfaces of plants could provide rich and underexplored opportunities for the discovery of novel bioactive metabolites.…”