Activation of fungal silent gene clusters: A new avenue to drug discovery

2008 ◽  
pp. 1-12 ◽  
Author(s):  
Axel A. Brakhage ◽  
Julia Schuemann ◽  
Sebastian Bergmann ◽  
Kirstin Scherlach ◽  
Volker Schroeckh ◽  
...  
Keyword(s):  
Drug Discovery ◽  
Gene Clusters ◽  
Silent Gene

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

Marine Drugs ◽  
2019 ◽  
Vol 17 (8) ◽  
pp. 446 ◽  
Author(s):  
Jing Yu ◽  
Huan Han ◽  
Xianyan Zhang ◽  
Chuanteng Ma ◽  
Chunxiao Sun ◽  
...  
Keyword(s):  
Mutant Strain ◽  
Morphological Changes ◽  
Gene Clusters ◽  
Fungal Strain ◽  
Chemical Investigation ◽  
Global Regulator ◽  
Silent Gene

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.

scholarly journals Integrated Genomic and Metabolomic Approach to the Discovery of Potential Anti-Quorum Sensing Natural Products from Microbes Associated with Marine Samples from Singapore

Marine Drugs ◽  
2019 ◽  
Vol 17 (1) ◽  
pp. 72 ◽  
Author(s):  
Ji Ong ◽  
Hui Goh ◽  
Swee Lim ◽  
Li Pang ◽  
Joyce Chin ◽  
...  
Keyword(s):  
Drug Discovery ◽  
Quorum Sensing ◽  
Large Scale ◽  
Marine Ecosystem ◽  
Gene Clusters ◽  
Integrated Approach ◽  
Rrna Gene ◽  
Dependent Manner ◽  
Bacterial Strains ◽  
Reporter System

With 70% of the Earth’s surface covered in water, the marine ecosystem offers immense opportunities for drug discovery and development. Due to the decreasing rate of novel natural product discovery from terrestrial sources in recent years, many researchers are beginning to look seaward for breakthroughs in new therapeutic agents. As part of an ongoing marine drug discovery programme in Singapore, an integrated approach of combining metabolomic and genomic techniques were initiated for uncovering novel anti-quorum sensing molecules from bacteria associated with subtidal samples collected in the Singapore Strait. Based on the culture-dependent method, a total of 102 marine bacteria strains were isolated and the identities of selected strains were established based on their 16S rRNA gene sequences. About 5% of the marine bacterial organic extracts showed quorum sensing inhibitory (QSI) activity in a dose-dependent manner based on the Pseudomonas aeruginosa QS reporter system. In addition, the extracts were subjected to mass spectrometry-based molecular networking and the genome of selected strains were analysed for known as well as new biosynthetic gene clusters. This study revealed that using integrated techniques, coupled with biological assays, can provide an effective and rapid prioritization of marine bacterial strains for downstream large-scale culturing for the purpose of isolation and structural elucidation of novel bioactive compounds.

scholarly journals Predatory Organisms with Untapped Biosynthetic Potential: Descriptions of Novel Corallococcus Species C. aberystwythensis sp. nov., C. carmarthensis sp. nov., C. exercitus sp. nov., C. interemptor sp. nov., C. llansteffanensis sp. nov., C. praedator sp. nov., C. sicarius sp. nov., and C. terminator sp. nov.

2019 ◽  
Vol 86 (2) ◽  
Author(s):  
Paul G. Livingstone ◽  
Oliver Ingleby ◽  
Susan Girdwood ◽  
Alan R. Cookson ◽  
Russell M. Morphew ◽  
...  
Keyword(s):  
Drug Discovery ◽  
Novel Species ◽  
Methyl Esters ◽  
Gene Clusters ◽  
Distinct Species ◽  
Antimicrobial Activities ◽  
Biologically Active ◽  
Active Metabolites ◽  
Taxonomic Assignment ◽  
Content Type

ABSTRACT Corallococcus spp. are common soil-dwelling organisms which kill and consume prey microbes through the secretion of antimicrobial substances. Two species of Corallococcus have been described previously (Corallococcus coralloides and Corallococcus exiguus). A polyphasic approach, including biochemical analysis of fatty acid methyl esters, substrate utilization, and sugar assimilation assays, was taken to characterize eight Corallococcus species strains and the two type strains. The genomes of all strains, including that of C. exiguus DSM 14696T (newly reported here), shared an average nucleotide identity below 95% and digital DNA-DNA hybridization scores of less than 70%, indicating that they belong to distinct species. In addition, we characterized the prey range and antibiotic resistance profile of each strain, illustrating the diversity of antimicrobial activity and, thus, the potential for drug discovery within the Corallococcus genus. Each strain gave a distinct profile of properties, which together with their genomic differences supports the proposal of the eight candidate strains as novel species. The eight candidates are as follows: Corallococcus exercitus sp. nov. (AB043AT = DSM 108849T = NBRC 113887T), Corallococcus interemptor sp. nov. (AB047AT = DSM 108843T = NBRC 113888T), Corallococcus aberystwythensis sp. nov. (AB050AT = DSM 108846T = NBRC 114019T), Corallococcus praedator sp. nov. (CA031BT = DSM 108841T = NBRC 113889T), Corallococcus sicarius sp. nov. (CA040BT = DSM 108850T = NBRC 113890T), Corallococcus carmarthensis sp. nov. (CA043DT = DSM 108842T = NBRC 113891T), Corallococcus llansteffanensis sp. nov. (CA051BT = DSM 108844T = NBRC 114100T), and Corallococcus terminator sp. nov. (CA054AT = DSM 108848T = NBRC 113892T). IMPORTANCE Corallococcus is a genus of predators with broad prey ranges, whose genomes contain large numbers of gene clusters for secondary metabolite biosynthesis. The physiology and evolutionary heritage of eight Corallococcus species strains were characterized using a range of analyses and assays. Multiple metrics confirmed that each strain belonged to a novel species within the Corallococcus genus. The strains exhibited distinct patterns of drug resistance and predatory activity, which mirrored their possession of diverse sets of biosynthetic genes. The breadth of antimicrobial activities observed within the Corallococcus genus highlights their potential for drug discovery and suggests a previous underestimation of both their taxonomic diversity and biotechnological potential. Taxonomic assignment of environmental isolates to novel species allows us to begin to characterize the diversity and evolution of members of this bacterial genus with potential biotechnological importance, guiding future bioprospecting efforts for novel biologically active metabolites and antimicrobials.

scholarly journals Genetically Modified Bacterial Strains and Novel Bacterial Artificial Chromosome Shuttle Vectors for Constructing Environmental Libraries and Detecting Heterologous Natural Products in Multiple Expression Hosts

2004 ◽  
Vol 70 (4) ◽  
pp. 2452-2463 ◽  
Author(s):  
Asuncion Martinez ◽  
Steven J. Kolvek ◽  
Choi Lai Tiong Yip ◽  
Joern Hopke ◽  
Kara A. Brown ◽  
...  
Keyword(s):  
Natural Products ◽  
Drug Discovery ◽  
Bacterial Artificial Chromosome ◽  
Environmental Dna ◽  
Gene Clusters ◽  
Artificial Chromosome ◽  
Bacterial Strains ◽  
Soil Dna ◽  
Shuttle Vectors ◽  
E Coli

ABSTRACT The enormous diversity of uncultured microorganisms in soil and other environments provides a potentially rich source of novel natural products, which is critically important for drug discovery efforts. Our investigators reported previously on the creation and screening of an Escherichia coli library containing soil DNA cloned and expressed in a bacterial artificial chromosome (BAC) vector. In that initial study, our group identified novel enzyme activities and a family of antibacterial small molecules encoded by soil DNA cloned and expressed in E. coli. To continue our pilot study of the utility and feasibility of this approach to natural product drug discovery, we have expanded our technology to include Streptomyces lividans and Pseudomonas putida as additional hosts with different expression capabilities, and herein we describe the tools we developed for transferring environmental libraries into all three expression hosts and screening for novel activities. These tools include derivatives of S. lividans that contain complete and unmarked deletions of the act and red endogenous pigment gene clusters, a derivative of P. putida that can accept environmental DNA vectors and integrate the heterologous DNA into the chromosome, and new BAC shuttle vectors for transferring large fragments of environmental DNA from E. coli to both S. lividans and P. putida by high-throughput conjugation. Finally, we used these tools to confirm that the three hosts have different expression capabilities for some known gene clusters.

scholarly journals Targeted induction of a silent fungal gene cluster encoding the bacteria-specific germination inhibitor fumigermin

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Maria Cristina Stroe ◽  
Tina Netzker ◽  
Kirstin Scherlach ◽  
Thomas Krüger ◽  
Christian Hertweck ◽  
...  
Keyword(s):  
Gene Cluster ◽  
Polyketide Synthase ◽  
Biological Activities ◽  
Gene Clusters ◽  
Ecological Function ◽  
The Novel ◽  
Ecological Context ◽  
Fungal Metabolite ◽  
Silent Gene ◽  
Encoding Gene

Microorganisms produce numerous secondary metabolites (SMs) with various biological activities. Many of their encoding gene clusters are silent under standard laboratory conditions because for their activation they need the ecological context, such as the presence of other microorganisms. The true ecological function of most SMs remains obscure, but understanding of both the activation of silent gene clusters and the ecological function of the produced compounds is of importance to reveal functional interactions in microbiomes. Here, we report the identification of an as-yet uncharacterized silent gene cluster of the fungus Aspergillus fumigatus, which is activated by the bacterium Streptomyces rapamycinicus during the bacterial-fungal interaction. The resulting natural product is the novel fungal metabolite fumigermin, the biosynthesis of which requires the polyketide synthase FgnA. Fumigermin inhibits germination of spores of the inducing S. rapamycinicus, and thus helps the fungus to defend resources in the shared habitat against a bacterial competitor.

scholarly journals Recent Advances in Silent Gene Cluster Activation in Streptomyces

2021 ◽  
Vol 9 ◽  
Author(s):  
Zhenyu Liu ◽  
Yatong Zhao ◽  
Chaoqun Huang ◽  
Yunzi Luo
Keyword(s):  
Natural Products ◽  
Gene Clusters ◽  
Biosynthetic Gene ◽  
Biosynthetic Gene Clusters ◽  
Heterologous Host ◽  
Silent Gene ◽  
Drug Molecules ◽  
Discovery Research ◽  
Natural Products Discovery ◽  
Native Host

Natural products (NPs) are critical sources of drug molecules for decades. About two-thirds of natural antibiotics are produced by Streptomyces. Streptomyces have a large number of secondary metabolite biosynthetic gene clusters (SM-BGCs) that may encode NPs. However, most of these BGCs are silent under standard laboratory conditions. Hence, activation of these silent BGCs is essential to current natural products discovery research. In this review, we described the commonly used strategies for silent BGC activation in Streptomyces from two aspects. One focused on the strategies applied in heterologous host, including methods to clone and reconstruct BGCs along with advances in chassis engineering; the other focused on methods applied in native host which includes engineering of promoters, regulatory factors, and ribosomes. With the metabolic network being elucidated more comprehensively and methods optimized more high-thoroughly, the discovery of NPs will be greatly accelerated.

scholarly journals Metabolomics and Marine Biotechnology: Coupling Metabolite Profiling and Organism Biology for the Discovery of New Compounds

2020 ◽  
Vol 7 ◽  
Author(s):  
Miriam Reverter ◽  
Sven Rohde ◽  
Christelle Parchemin ◽  
Nathalie Tapissier-Bontemps ◽  
Peter J. Schupp
Keyword(s):  
Drug Discovery ◽  
Metabolite Identification ◽  
Gene Clusters ◽  
Chemical Diversity ◽  
Molecular Networks ◽  
Marine Biotechnology ◽  
Bioinformatic Tools ◽  
Large Sets ◽  
Metabolite Synthesis ◽  
New Compounds

The high diversity of marine natural products represents promising opportunities for drug discovery, an important area in marine biotechnology. Within this context, high-throughput techniques such as metabolomics are extremely useful in unveiling unexplored chemical diversity at much faster rates than classical bioassay-guided approaches. Metabolomics approaches enable studying large sets of metabolites, even if they are produced at low concentrations. Although, metabolite identification remains the main metabolomics bottleneck, bioinformatic tools such as molecular networks can lead to the annotation of unknown metabolites and discovery of new compounds. A metabolomic approach in drug discovery has two major advantages: it enables analyses of multiple samples, allowing fast dereplication of already known compounds and provides a unique opportunity to relate metabolite profiles to organisms’ biology. Understanding the ecological and biological factors behind a certain metabolite production can be extremely useful in enhancing compound yields, optimizing compound extraction or in selecting bioactive compounds. Metazoan-associated microbiota are often responsible for metabolite synthesis, however, classical approaches only allow studying metabolites produced from cultivatable microbiota, which often differ from the compounds produced within the host. Therefore, coupling holobiome metabolomics with microbiome analysis can bring new insights to the role of microbiota in compound production. The ultimate potential of metabolomics is its coupling with other “omics” (i.e., transcriptomics and metagenomics). Although, such approaches are still challenging, especially in non-model species where genomes have not been annotated, this innovative approach is extremely valuable in elucidating gene clusters associated with biosynthetic pathways and will certainly become increasingly important in marine drug discovery.

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