Discovery of Two New Sorbicillinoids by Overexpression of the Global Regulator LaeA in a Marine-Derived Fungus Penicillium dipodomyis YJ-11

Huan Han,Xianyan Zhang,Qian Che,Qianqun Gu,Chuanteng Ma,Jing Yu,Dehai Li,Guojian Zhang,Chunxiao Sun,Tianjiao Zhu

doi:10.3390/md17080446

Abstract

Overexpression of the global regulator LaeA in a marine-derived fungal strain of Penicillium dipodomyis YJ-11 induced obvious morphological changes and metabolic variations. Further chemical investigation of the mutant strain afforded a series of sorbicillinoids including two new ones named 10,11-dihydrobislongiquinolide (1) and 10,11,16,17-tetrahydrobislongiquinolide (2), as well as four known analogues, bislongiquinolide (3), 16,17-dihydrobislongiquinolide (4), sohirnone A (5), and 2′,3′-dihydrosorbicillin (6). The results support that the global regulator LaeA is a useful tool in activating silent gene clusters in Penicillium strains to obtain previously undiscovered compounds.

Highlights

Filamentous fungi have proven to be important sources of bioactive natural products for development of new drug leads
As the traditional approach has been continuously applied in discovery of new secondary metabolites, it has become a frequent issue that known structures are repeatedly discovered, while a big portion of biosynthetic genes are not expressed under current culturing technologies termed as “silent” or “cryptic” genes
To increase the silent metabolic potential of the microbial producers, a variety of approaches such as heterologous expression, epigenetic regulation, transcriptional regulation and ribosome engineering, have been developed to affect the biosynthetic process in different gene regulation levels [1,2,3], among which, transcriptional factor regulation is often adopted because it is feasible and effective, and from which unexpected new secondary metabolites could be obtained by activation of the silent genes

Summary

Introduction

Filamentous fungi have proven to be important sources of bioactive natural products for development of new drug leads. As the traditional approach (cultivation of microorganisms, chemical extraction of the produced metabolites, and final structure and bioactivity elucidations) has been continuously applied in discovery of new secondary metabolites, it has become a frequent issue that known structures are repeatedly discovered, while a big portion of biosynthetic genes are not expressed under current culturing technologies termed as “silent” or “cryptic” genes. To increase the silent metabolic potential of the microbial producers, a variety of approaches such as heterologous expression, epigenetic regulation, transcriptional regulation and ribosome engineering, have been developed to affect the biosynthetic process in different gene regulation levels [1,2,3], among which, transcriptional factor regulation is often adopted because it is feasible and effective, and from which unexpected new secondary metabolites could be obtained by activation of the silent genes. LaeA gene analogues with similar functions were reported from other fungal species such as Penicillium chrysogenum [10], Monascus ruber [11], Alternaria alternate [12], and Dothistroma septosporum [8]

Methods

Results

Conclusion