Halogenase-Targeted Genome Mining Leads to the Discovery of (±) Pestalachlorides A1a, A2a, and Their Atropisomers

Abstract

Genome mining has become an important tool for discovering new natural products and identifying the cryptic biosynthesis gene clusters. Here, we utilized the flavin-dependent halogenase GedL as the probe in combination with characteristic halogen isotope patterns to mine new halogenated secondary metabolites from our in-house fungal database. As a result, two pairs of atropisomers, pestalachlorides A1a (1a)/A1b (1b) and A2a (2a)/A2b (2b), along with known compounds pestalachloride A (3) and SB87-H (4), were identified from Pestalotiopsis rhododendri LF-19-12. A plausible biosynthetic assembly line for pestalachlorides involving a putative free-standing phenol flavin-dependent halogenase was proposed based on bioinformatics analysis. Pestalachlorides exhibited antibacterial activity against sensitive and drug-resistant S. aureus and E. faecium with MIC values ranging from 4 μg/mL to 32 μg/mL. This study indicates that halogenase-targeted genome mining is an efficient strategy for discovering halogenated compounds and their corresponding halogenases.

A Survey of Recently Discovered Naturally Occurring Organohalogen Compounds

“…Phomopchalasin E is cytotoxic toward MDA-MB-455 cancer cells (IC 50 7.4 μM) . The new atropisomeric (±)-pestachlorides Ala/Alb ( 357 / 358 ), A2a/A2b ( 359 / 360 ), and A ( 361 ) are found in a culture of Pestalotiopsis rhododendri LF-19–12, a fungus living on a Chinese lichen sample in Tibet . The Cameroon plant Caloncoba welwitschii is host to the fungus Pseudopestalotiopsis theae that contains the new sydoxanthone E ( 362 ) …”

“…167 The new atropisomeric (±)-pestachlorides Ala/Alb (357/358), A2a/ A2b (359/360), and A (361) are found in a culture of Pestalotiopsis rhododendri LF-19−12, a fungus living on a Chinese lichen sample in Tibet. 168 The Cameroon plant Caloncoba welwitschii is host to the fungus Pseudopestalotiopsis theae that contains the new sydoxanthone E (362). 169 The endophytic fungus Aspergillus unguis BCC54176 is home to four new aspergillusethers G−J (363−366) and the new emeguisin D (367), together with 18 known analogues.…”

Discovery and excavation of lichen bioactive natural products

“…If it is the common fact that is not easily solved now about the conflict between more lichen natural products by OSMAC from LFF cultures and uncertain or not very well bioactivity compared with those isolated from lichen thallus, genome mining-based strategy will be a more explicit way to discover lichen natural products. With the development of bioinformatics and the applying next-generation sequencing data, there has indeed been more focus on natural product discovery based on genomics (Garima et al, 2022b ; Luo et al, 2022 ). Genome mining has become a powerful tool to discover compounds, identify cryptic biosynthetic gene clusters, characterize the potential biosynthetic pathways, and predict the skeletal structure of the relative products (Liu Q. et al, 2022 ; Liu T. et al, 2022 ; Kalra et al, 2023 ).…”

Nocaviogua A and B: two lipolanthines from root-nodule-associated Nocardia sp.

“…In our continuing efforts to explore novel bioactive metabolites from unique habitat-derived microbes (Chang et al, 2022a;Luo et al, 2022a;Chang et al, 2022b;Luo et al, 2022b), two lipolanthines (1 and 2) were produced by Nocardia sp. XZ19_369, which was isolated from the nodules of sea buckthorn collected in Tibet, China.…”