scholarly journals New strategies for drug discovery: activation of silent or weakly expressed microbial gene clusters

2012 ◽  
Vol 97 (1) ◽  
pp. 87-98 ◽  
Author(s):  
Kozo Ochi ◽  
Takeshi Hosaka
Keyword(s):  
Drug Discovery ◽  
Gene Clusters ◽  
New Strategies

scholarly journals Beyond Antioxidant Effects: Nature-Based Templates Unveil New Strategies for Neurodegenerative Diseases

Antioxidants ◽  
2021 ◽  
Vol 10 (3) ◽  
pp. 367
Author(s):  
Andrea Bacci ◽  
Massimiliano Runfola ◽  
Simona Sestito ◽  
Simona Rapposelli
Keyword(s):  
Drug Discovery ◽  
Neurodegenerative Diseases ◽  
Redox Reactions ◽  
Identification Process ◽  
Defense Systems ◽  
Natural Defense ◽  
Effective Drugs ◽  
Antioxidant Effects ◽  
Neuronal Disorders ◽  
New Strategies

The complex network of malfunctioning pathways occurring in the pathogenesis of neurodegenerative diseases (NDDs) represents a huge hurdle in the development of new effective drugs to be used in therapy. In this context, redox reactions act as crucial regulators in the maintenance of neuronal microenvironment homeostasis. Particularly, their imbalance results in the severe compromising of organism’s natural defense systems and subsequently, in the instauration of deleterious OS, that plays a fundamental role in the insurgence and progress of NDDs. Despite the huge efforts in drug discovery programs, the identification process of new therapeutic agents able to counteract the relentless progress of neurodegenerative processes has produced low or no effective therapies. Consequently, a paradigm-shift in the drug discovery approach for these diseases is gradually occurring, paving the way for innovative therapeutical approaches, such as polypharmacology. The aim of this review is to provide an overview of the main pharmacological features of most promising nature-based scaffolds for a possible application in drug discovery, especially for NDDs, highlighting their multifaceted effects against OS and neuronal disorders.

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 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 New sources of drugs for hematologic malignancies

Blood ◽  
2011 ◽  
Vol 117 (25) ◽  
pp. 6747-6755 ◽  
Author(s):  
Mahadeo A. Sukhai ◽  
Paul A. Spagnuolo ◽  
Scott Weir ◽  
James Kasper ◽  
Lavonne Patton ◽  
...  
Keyword(s):  
Drug Discovery ◽  
Early Stage ◽  
Low Cost ◽  
Drug Repurposing ◽  
Hematologic Malignancies ◽  
Charitable Organizations ◽  
Biotechnology Companies ◽  
Old Drugs ◽  
New Strategies ◽  
Lengthy Process

Abstract Advancing novel therapeutic agents for the treatment of malignancy into the marketplace is an increasingly costly and lengthy process. As such, new strategies for drug discovery are needed. Drug repurposing represents an opportunity to rapidly advance new therapeutic strategies into clinical trials at a relatively low cost. Known on-patent or off-patent drugs with unrecognized anticancer activity can be rapidly advanced into clinical testing for this new indication by leveraging their known pharmacology, pharmacokinetics, and toxicology. Using this approach, academic groups can participate in the drug discovery field and smaller biotechnology companies can “de-risk” early-stage drug discovery projects. Here, several scientific approaches used to identify drug repurposing opportunities are highlighted, with a focus on hematologic malignancies. In addition, a discussion of the regulatory issues that are unique to drug repurposing and how they impact developing old drugs for new indications is included. Finally, the mechanisms to enhance drug repurposing through increased collaborations between academia, industry, and nonprofit charitable organizations are discussed.

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