Use of a genetic dereplication strategy eliminates major known SM biosynthetic pathways in Aspergillus nidulans, reducing the complexity of SM profiles and activating an abundance of silent SM gene clusters to enable identification of a new pool of fungal products for drug discovery.
The filamentous fungus Aspergillus nidulans is a commonly used model fungus for drug discovery and development due to its advanced, highly efficient molecular genetic system. This species and related organisms produce secondary metabolites (SMs), low molecular weight molecules with a variety of biological activities, which are used to develop medically useful compounds including antibiotics, immunosupressants, antifungals, and antihypercholesterolemic drugs. Most easily accessible, bioactive SMs have been isolated and developed for therapeutic use. However, advances in genome sequencing show that fungal species harbor an abundance of SM gene clusters, which far exceed the number of known metabolites produced by the species. Activating these silent gene clusters, revealing their biosynthetic pathways, and isolating the SMs produced by these pathways is a major challenge in the search for new SMs. Although genetic and molecular genetic approaches which upregulate secondary metabolite production have dramatically facilitated the discovery of new fungal natural products for medical use and other purposes, these approaches often result in complex metabolite profiles with large numbers of compounds and pathway intermediates.
Activation of silent SM gene clusters enables investigation of a new pool of fungal products for drug discovery.
How it works:
Genetic dereplication is used to simplify the discovery of new compounds by eliminating major known SM biosynthetic pathways in Aspergillus nidulans, reducing profile complexity and background intermediates to enable easy detection of new compounds and elimination of toxic products. Elimination of highly expressed biosynthetic pathways reserves pools of SM precursors for pathways expressed at low levels. Deletion of the major secondary metabolite gene clusters (240,000 base pairs) enabled identification of novel compounds, which are differentially regulated and capable of producing SMs that are suitable for human/animal use and incapable of producing major toxic products. Increasing identification of new compounds paves the way for the discovery of much needed potent, novel natural therapeutics.
A unique, less time consuming strategy for reducing the complexity of SM biosynthetic profiles in Aspergillus nidulans to facilítate the detection of novel compounds produced through heterologous expression of SM genes and detection of genes that regulate cryptic SM clusters.
Why it is better:
Use of this strategy reduces secondary metabolite background facilitating the production of secondary metabolites and eliminating the production of toxic products.
Elucidation of new natural products allows for the potential identification of a variety of new drugs in a wide variety of therpaeutic areas. Previously, SMs identified in Aspergillus nidulans have been used to develop antibiotics, immunosupressants, antifungals, and antihypercholesterolemic drugs.