scholarly journals Improving Fungal Cultivability for Natural Products Discovery

2021 ◽  
Vol 12 ◽  
Author(s):  
Teppo Rämä ◽  
C. Alisha Quandt
Keyword(s):  
Natural Products ◽  
Growth Factors ◽  
Drug Discovery ◽  
Culture Media ◽  
Gene Clusters ◽  
Physical Factors ◽  
Culture Collections ◽  
Biological Assays ◽  
Increased Risk

The pool of fungal secondary metabolites can be extended by activating silent gene clusters of cultured strains or by using sensitive biological assays that detect metabolites missed by analytical methods. Alternatively, or in parallel with the first approach, one can increase the diversity of existing culture collections to improve the access to new natural products. This review focuses on the latter approach of screening previously uncultured fungi for chemodiversity. Both strategies have been practiced since the early days of fungal biodiscovery, yet relatively little has been done to overcome the challenge of cultivability of as-yet-uncultivated fungi. Whereas earlier cultivability studies using media formulations and biological assays to scrutinize fungal growth and associated factors were actively conducted, the application of modern omics methods remains limited to test how to culture the fungal dark matter and recalcitrant groups of described fungi. This review discusses the development of techniques to increase the cultivability of filamentous fungi that include culture media formulations and the utilization of known chemical growth factors, in situ culturing and current synthetic biology approaches that build upon knowledge from sequenced genomes. We list more than 100 growth factors, i.e., molecules, biological or physical factors that have been demonstrated to induce spore germination as well as tens of inducers of mycelial growth. We review culturing conditions that can be successfully manipulated for growth of fungi and visit recent information from omics methods to discuss the metabolic basis of cultivability. Earlier work has demonstrated the power of co-culturing fungi with their host, other microorganisms or their exudates to increase their cultivability. Co-culturing of two or more organisms is also a strategy used today for increasing cultivability. However, fungi possess an increased risk for cross-contaminations between isolates in existing in situ or microfluidics culturing devices. Technological improvements for culturing fungi are discussed in the review. We emphasize that improving the cultivability of fungi remains a relevant strategy in drug discovery and underline the importance of ecological and taxonomic knowledge in culture-dependent drug discovery. Combining traditional and omics techniques such as single cell or metagenome sequencing opens up a new era in the study of growth factors of hundreds of thousands of fungal species with high drug discovery potential.

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 On the Risks of Phylogeny-Based Strain Prioritization for Drug Discovery: Streptomyces lunaelactis as a Case Study

Biomolecules ◽  
2020 ◽  
Vol 10 (7) ◽  
pp. 1027 ◽  
Author(s):  
Loïc Martinet ◽  
Aymeric Naômé ◽  
Dominique Baiwir ◽  
Edwin De Pauw ◽  
Gabriel Mazzucchelli ◽  
...  
Keyword(s):  
Natural Products ◽  
Drug Discovery ◽  
Reference Strain ◽  
Pattern Analysis ◽  
Genome Mining ◽  
Gene Clusters ◽  
Biosynthetic Gene ◽  
Biosynthetic Gene Clusters ◽  
Representative Strain

Strain prioritization for drug discovery aims at excluding redundant strains of a collection in order to limit the repetitive identification of the same molecules. In this work, we wanted to estimate what can be unexploited in terms of the amount, diversity, and novelty of compounds if the search is focused on only one single representative strain of a species, taking Streptomyces lunaelactis as a model. For this purpose, we selected 18 S. lunaelactis strains taxonomically clustered with the archetype strain S. lunaelactis MM109T. Genome mining of all S. lunaelactis isolated from the same cave revealed that 54% of the 42 biosynthetic gene clusters (BGCs) are strain specific, and five BGCs are not present in the reference strain MM109T. In addition, even when a BGC is conserved in all strains such as the bag/fev cluster involved in bagremycin and ferroverdin production, the compounds produced highly differ between the strains and previously unreported compounds are not produced by the archetype MM109T. Moreover, metabolomic pattern analysis uncovered important profile heterogeneity, confirming that identical BGC predisposition between two strains does not automatically imply chemical uniformity. In conclusion, trying to avoid strain redundancy based on phylogeny and genome mining information alone can compromise the discovery of new natural products and might prevent the exploitation of the best naturally engineered producers of specific molecules.

Expanding the Natural Products Heterologous Expression Repertoire in the Model Cyanobacterium Anabaena sp. Strain PCC 7120: Production of Pendolmycin and Teleocidin B-4

2019 ◽  
Author(s):  
Patrick Videau ◽  
Kaitlyn Wells ◽  
Arun Singh ◽  
Jessie Eiting ◽  
Philip Proteau ◽  
...  
Keyword(s):  
Natural Products ◽  
Genome Mining ◽  
Gene Clusters ◽  
Combinatorial Biosynthesis ◽  
Test Case ◽  
Biosynthetic Gene ◽  
Biosynthetic Gene Clusters ◽  
Cyanobacterium Anabaena ◽  
Anabaena Sp ◽  
Pcc 7120

Cyanobacteria are prolific producers of natural products and genome mining has shown that many orphan biosynthetic gene clusters can be found in sequenced cyanobacterial genomes. New tools and methodologies are required to investigate these biosynthetic gene clusters and here we present the use of <i>Anabaena </i>sp. strain PCC 7120 as a host for combinatorial biosynthesis of natural products using the indolactam natural products (lyngbyatoxin A, pendolmycin, and teleocidin B-4) as a test case. We were able to successfully produce all three compounds using codon optimized genes from Actinobacteria. We also introduce a new plasmid backbone based on the native <i>Anabaena</i>7120 plasmid pCC7120ζ and show that production of teleocidin B-4 can be accomplished using a two-plasmid system, which can be introduced by co-conjugation.

Main approaches to prevention of health disorders in workers in contact with physical factors

2020 ◽  
Vol 60 (11) ◽  
pp. 827-829
Author(s):  
Andrey V. Melentyev
Keyword(s):  
Cardiovascular Risk ◽  
Cardiovascular Diseases ◽  
Machine Building ◽  
Working Environment ◽  
Physical Factors ◽  
Noise And Vibration ◽  
Industrial Enterprises ◽  
Increased Risk ◽  
Health Disorders ◽  
Building Enterprises

Introduction. One of the leading causes of occupational health loss, especially in mining and machine-building enterprises, is the combined impact of industrial noise and vibration. The wide prevalence of cardiovascular diseases is one of the most important medical and social problems, due to persistent disability and high mortality, bringing prevention of health disorders to the first place as the basis for preserving labor longevity. The aim of study is to identify the main approaches aimed at preventing health problems in workers who come into contact with vibration and noise at mining and machine-building enterprises. Materials and methods. A survey and survey of 296 industrial workers was conducted. Group 1 (160 people) included men who were exposed to noise and vibration factors above the maximum permissible levels, group 2 consisted of 136 men who did not have direct contact with noise and vibration generating equipment. When conducting an in-depth laboratory and instrumental examination in a hospital setting, all workers additionally calculated the level of cardiovascular risk on the SCORE scale. Statistical analysis was performed using the software package "Statistica 6.0". Results. It is determined that the priority adverse factors of the working environment in production are noise and vibration. It has been shown that individuals who come into contact with these factors are more likely to detect violations of lipid metabolism and endothelial function, have a higher average heart rate and systolic blood pressure, and have an increased risk of developing cardiovascular diseases. Conclusions. Taking into account the obtained results of the proposed diagnostic approaches aimed at the prevention of health disorders among workers of industrial enterprises. If employees are found to have an increased cardiovascular risk, it is necessary to conduct a more in-depth examination and timely medical and preventive measures.

scholarly journals Partitioning Pattern of Natural Products Based on Molecular Properties Descriptors Representing Drug-Likeness

Symmetry ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 546
Author(s):  
Miroslava Nedyalkova ◽  
Vasil Simeonov
Keyword(s):  
Natural Products ◽  
Drug Discovery ◽  
De Novo ◽  
Target Prediction ◽  
Natural Compounds ◽  
Discovery Process ◽  
Drug Discovery Process ◽  
Unique Source ◽  
The Times ◽  
Partitioning Pattern

A cheminformatics procedure for a partitioning model based on 135 natural compounds including Flavonoids, Saponins, Alkaloids, Terpenes and Triterpenes with drug-like features based on a descriptors pool was developed. The knowledge about the applicability of natural products as a unique source for the development of new candidates towards deadly infectious disease is a contemporary challenge for drug discovery. We propose a partitioning scheme for unveiling drug-likeness candidates with properties that are important for a prompt and efficient drug discovery process. In the present study, the vantage point is about the matching of descriptors to build the partitioning model applied to natural compounds with diversity in structures and complexity of action towards the severe diseases, as the actual SARS-CoV-2 virus. In the times of the de novo design techniques, such tools based on a chemometric and symmetrical effect by the implied descriptors represent another noticeable sign for the power and level of the descriptors applicability in drug discovery in establishing activity and target prediction pipeline for unknown drugs properties.

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