Screening and identification of novel biologically active natural compounds

Abstract

With the advent of very rapid and cheap genome analyses and the linkage of these plus microbial metabolomics to potential compound structures came the realization that there was an immense sea of novel agents to be mined and tested. In addition, it is now recognized that there is significant microbial involvement in many natural products isolated from “nominally non-microbial sources”. This short review covers the current screening methods that have evolved and one might even be tempted to say “devolved” in light of the realization that target-based screens had problems when the products entered clinical testing, with off-target effects being the major ones. Modern systems include, but are not limited to, screening in cell lines utilizing very modern techniques (a high content screen) that are designed to show interactions within cells when treated with an “agent”. The underlying principle(s) used in such systems dated back to unpublished attempts in the very early 1980s by the pharmaceutical industry to show toxic interactions within animal cells by using automated light microscopy. Though somewhat successful, the technology was not adequate for any significant commercialization. Somewhat later, mammalian cell lines that were “genetically modified” to alter signal transduction cascades, either up or down, and frequently linked to luciferase readouts, were then employed in a 96-well format. In the case of microbes, specific resistance parameters were induced in isogenic cell lines from approximately the mid-1970s. In the latter two cases, comparisons against parent and sibling cell lines were used in order that a rapid determination of potential natural product “hits” could be made. Obviously, all of these assay systems could also be, and were, used for synthetic molecules. These methods and their results have led to a change in what the term “screening for bioactivity” means. In practice, versions of phenotypic screening are returning, but in a dramatically different scientific environment from the 1970s, as I hope to demonstrate in the short article that follows.

Novel applications of mass spectrometry‐based metabolomics in herbal medicines and its active ingredients: Current evidence

“…In the past few decades, the discovery and development model of bioactive natural products has changed from the determination of phytochemistry of plants to the use of advanced analytical techniques, genomics, and metabolomics combined with high‐throughput and high‐content screening (Newman, ). Metabolomics as a rapid screening method provides an efficacious way to discover bioactive ingredients from herbal medicines.…”

Application of Image-Based High Content Analysis for the Screening of Bioactive Natural Products

“…The first screen covered isolated metabolites from marine sponges (Jaspis splendens) to prove that the overall system could function. The following screen then utilized a 500-plus pure compound set from the Nature Bank collection at Griffith University [1,4,29,30]. The results demonstrated that such a HCS produced multiple possibilities for the identification of the interaction(s) with cellular organelles/protein interactions, being limited only by the specificity of the fluorescent probes used to demonstrate the responses.…”

“…Reasons for this fact are related to the lack of expertise and infrastructure for biological screening, high costs as well as time consuming if samples must be sent to overseas laboratories. It is therefore highly desirable to develop in-house bioassays in institutes for chemical research which are inexpensive, rapid and do not require the chemists a specialized knowledge of biology or pharmacology [1][2][3]. The bioassay laboratories at Vietnam Academy of Science and Technology (VAST) had therefore initially established the "bench-top" bioassays since the 1990s.…”

Genome Mining of the Genus Streptacidiphilus for Biosynthetic and Biodegradation Potential

“…With the advancement in the genome sequencing technology, it was revealed that microorganisms still represent an essential source for novel natural products that need to be explored [ 19 ]. For example, the genome information of two well-studied species, Streptomyces coelicolor A3(2) [ 3 ] and Streptomyces avermitilis [ 20 ], revealed the presence of several cryptic biosynthetic gene clusters (BGCs), thereby highlighting their potential to produce new metabolites in addition to the existing ones from these organisms [ 21 ].…”