Opportunities for natural products in 21st century antibiotic discovery

2017 ◽  
Vol 34 (7) ◽  
pp. 694-701 ◽  
Author(s):  
Gerard D. Wright
Keyword(s):  
Natural Products ◽  
Natural Product ◽  
21St Century ◽  
New Drugs ◽  
Natural Product Research ◽  
Antibiotic Discovery

Natural product research is poised to regain prominence in delivering new drugs to solve the antibiotic crisis.

scholarly journals A practical guide for transparent reporting of research on natural products in the British Journal of Pharmacology : Reproducibility of natural product research

2020 ◽  
Vol 177 (10) ◽  
pp. 2169-2178 ◽  
Author(s):  
Angelo A. Izzo ◽  
Mauro Teixeira ◽  
Steve P.H. Alexander ◽  
Giuseppe Cirino ◽  
James R. Docherty ◽  
...  
Keyword(s):  
Natural Products ◽  
British Journal ◽  
Natural Product ◽  
Practical Guide ◽  
Transparent Reporting ◽  
Natural Product Research

Something old, something new: revisiting natural products in antibiotic drug discovery

2014 ◽  
Vol 60 (3) ◽  
pp. 147-154 ◽  
Author(s):  
Gerard D. Wright
Keyword(s):  
Natural Products ◽  
New Drugs ◽  
Clinical Use ◽  
Antibiotic Resistant ◽  
Antibiotic Drug ◽  
New Antibiotics ◽  
Bacteria And Fungi ◽  
Antibiotic Discovery ◽  
Novel Drug ◽  
New Strategies

Antibiotic discovery is in crisis. Despite a growing need for new drugs resulting from the increasing number of multi-antibiotic-resistant pathogens, there have been only a handful of new antibiotics approved for clinical use in the past 2 decades. Faced with scientific, economic, and regulatory challenges, the pharmaceutical sector seems unable to respond to what has been called an “apocalyptic” threat. Natural products produced by bacteria and fungi are genetically encoded products of natural selection that have been the mainstay sources of the antibiotics in current clinical use. The pharmaceutical industry has largely abandoned these compounds in favor of large libraries of synthetic molecules because of difficulties in identifying new natural product antibiotics scaffolds. Advances in next-generation genome sequencing, bioinformatics, and analytical chemistry are combining to overcome barriers to natural products. Coupled with new strategies in antibiotic discovery, including inhibition of resistance, novel drug combinations, and new targets, natural products are poised for a renaissance to address what is a pressing health care crisis.

scholarly journals Cheminformatics Analysis of Natural Product Scaffolds: Comparison of Scaffolds Produced by Animals, Plants, Fungi and Bacteria

2020 ◽  
Author(s):  
Peter Ertl ◽  
Tim Schuhmann
Keyword(s):  
Natural Products ◽  
Natural Selection ◽  
Natural Product ◽  
Selection Process ◽  
Structural Features ◽  
New Drugs ◽  
Large Database ◽  
Biologically Relevant ◽  
Different Types ◽  
Selection Of

AbstractNatural products (NPs) have evolved over a very long natural selection process to form optimal interactions with biologically relevant macromolecules. NPs are therefore an extremely useful source of inspiration for the design of new drugs. In the present study we report the results of a cheminformatics analysis of a large database of NP structures focusing on their scaffolds. First, general differences between NP scaffolds and scaffolds from synthetic molecules are discussed, followed by a comparison of the properties of scaffolds produced by different types of organisms. Scaffolds produced by plants are the most complex and those produced by bacteria differ in many structural features from scaffolds produced by other organisms. The results presented here may be used as a guidance in selection of scaffolds for the design of novel NP-like bioactive structures or NP-inspired libraries.

scholarly journals Ecopharmacognosy: Exploring The Chemical And Biological Potential Of Nature For Human Health

2014 ◽  
Vol 3 (1) ◽  
pp. 1 ◽  
Author(s):  
Geoffrey A. Cordell
Keyword(s):  
Health Care ◽  
Natural Products ◽  
Drug Discovery ◽  
Natural Product ◽  
Developed Countries ◽  
Biologically Active ◽  
Minor Role ◽  
Natural Product Research ◽  
Biological Potential ◽  
The World

“Why didn’t they develop natural product drugs in a sustainable manner at the beginning of this century?”  In 2035, when about 10.0 billion will inhabit Earth, will this be our legacy as the world contemplates the costs and availability of synthetic and gene-based products for primary health care?  Acknowledging the recent history of the relationship between humankind and the Earth, it is essential that the health care issues being left for our descendants be considered in terms of resources. For most people in the world, there are two vast health care “gaps”, access to quality drugs and the development of drugs for major global and local diseases.  Consequently for all of these people, plants, in their various forms, remain a primary source of health care.  In the developed countries, natural products derived from plants assume a relatively minor role in health care, as prescription and over-the-counter products, even with the widespread use of phytotherapeutical preparations.  Significantly, pharmaceutical companies have retrenched substantially in their disease areas of focus.  These research areas do not include the prevalent diseases of the middle- and lower-income countries, and important diseases of the developed world, such as drug resistance. What then is the vision for natural product research to maintain the choices of drug discovery and pharmaceutical development for future generations?  In this discussion some facets of how natural products must be involved globally, in a sustainable manner, for improving health care will be examined within the framework of the new term “ecopharmacognosy”, which invokes sustainability as the basis for research on biologically active natural products.  Access to the biome, the acquisition, analysis and dissemination of plant knowledge, natural product structure diversification, biotechnology development, strategies for natural product drug discovery, and aspects of multitarget therapy and synergy research will be discussed.  Options for the future will be presented which may be significant as countries decide how to develop approaches to relieve their own disease burden, and the needs of their population for improved access to medicinal agents.

scholarly journals Development of an agar-plug cultivation system for bioactivity assays of actinomycete strain collections

PLoS ONE ◽  
2021 ◽  
Vol 16 (11) ◽  
pp. e0258934
Author(s):  
Nico Ortlieb ◽  
Elke Klenk ◽  
Andreas Kulik ◽  
Timo Horst Johannes Niedermeyer
Keyword(s):  
Natural Products ◽  
Natural Product ◽  
Microtiter Plate ◽  
Growth Media ◽  
Natural Product Research ◽  
Solid Media ◽  
Agar Plug ◽  
Strain Collection ◽  
Actinomycete Strain ◽  
Initial Medium

Natural products are an important source of lead compounds for the development of drug substances. Actinomycetes have been valuable especially for the discovery of antibiotics. Increasing occurrence of antibiotic resistance among bacterial pathogens has revived the interest in actinomycete natural product research. Actinobacteria produce a different set of natural products when cultivated on solid growth media compared with submersed culture. Bioactivity assays involving solid media (e.g. agar-plug assays) require manual manipulation of the strains and agar plugs. This is less convenient for the screening of larger strain collections of several hundred or thousand strains. Thus, the aim of this study was to develop a 96-well microplate-based system suitable for the screening of actinomycete strain collections in agar-plug assays. We developed a medium-throughput cultivation and agar-plug assay workflow that allows the convenient inoculation of solid agar plugs with actinomycete spore suspensions from a strain collection, and the transfer of the agar plugs to petri dishes to conduct agar-plug bioactivity assays. The development steps as well as the challenges that were overcome during the development (e.g. system sterility, handling of the agar plugs) are described. We present the results from one exemplary screening campaign targeted to identify compounds inhibiting Agr-based quorum sensing where the workflow was used successfully. We present a novel and convenient workflow to combine agar diffusion assays with microtiter-plate-based cultivation systems in which strains can grow on a solid surface. This workflow facilitates and speeds up the initial medium throughput screening of natural product-producing actinomycete strain collections against monitor strains in agar-plug assays.

scholarly journals Type S Non Ribosomal Peptide Synthetases for the rapid generation of tailor-made peptide libraries

2021 ◽  
Author(s):  
Nadya Abbood ◽  
Tien Duy Vo ◽  
Jonas Watzel ◽  
Kenan A. J. Bozhueyuek ◽  
Helge B. Bode
Keyword(s):  
Natural Products ◽  
Natural Product ◽  
De Novo ◽  
Chemical Space ◽  
Biologically Relevant ◽  
Peptide Synthetases ◽  
Medical Needs ◽  
Natural Product Research ◽  
Rapid Generation ◽  
Traditional Natural

Bacterial natural products in general, and non-ribosomally synthesized peptides in particular, are structurally diverse and provide us with a broad range of pharmaceutically relevant bioactivities. Yet, traditional natural product research suffers from rediscovering the same scaffolds and has been stigmatised as inefficient, time-, labour-, and cost-intensive. Combinatorial chemistry, on the other hand, can produce new molecules in greater numbers, cheaper and in less time than traditional natural product discovery, but also fails to meet current medical needs due to the limited biologically relevant chemical space that can be addressed. Consequently, methods for the high throughput generation of new-to-nature natural products would offer a new approach to identifying novel bioactive chemical entities for the hit to lead phase of drug discovery programms. As a follow-up to our previously published proof-of-principle study on generating bipartite type S non-ribosomal peptide synthetases (NRPSs), we now envisaged the de novo generation of non-ribosomal peptides (NRPs) on an unreached scale. Using synthetic zippers, we split NRPS in up to three subunits and rapidly generated different bi- and tripartite NRPS libraries to produce 49 peptides, peptide derivatives, and de novo peptides at good titres up to 145 mgL-1. A further advantage of type S NRPSs not only is the possibility to easily expand the created libraries by re-using previously created type S NRPS, but that functions of individual domains as well as domain-domain interactions can be studied and assigned rapidly.

A Recent Look into Natural Products that have Potential to Inhibit Cholinesterases and Monoamine Oxidase B: Update for 2010-2019

2020 ◽  
Vol 23 (9) ◽  
pp. 862-876
Author(s):  
Hayrettin O. Gulcan ◽  
Ilkay E. Orhan
Keyword(s):  
Natural Products ◽  
Monoamine Oxidase ◽  
Natural Product ◽  
Biological Activities ◽  
Treatment Options ◽  
Monoamine Oxidase B ◽  
Chemical Structures ◽  
Natural Agents ◽  
Natural Product Research ◽  
Multiple Receptors

With respect to the unknowns of pathophysiology of Alzheimer’s Disease (AD)-, and Parkinson’s Disease (PD)-like neurodegenerative disorders, natural product research is still one of the valid tools in order to provide alternative and/or better treatment options. At one hand, various extracts of herbals provide a combination of actions targeting multiple receptors, on the other hand, the discovery of active natural products (i.e., secondary metabolites) generally offers alternative chemical structures either ready to be employed in clinical studies or available to be utilized as important scaffolds for the design of novel agents. Regarding the importance of certain enzymes (e.g. cholinesterase and monoamine oxidase B), for the treatment of AD and PD, we have surveyed the natural product research within this area in the last decade. Particularly novel natural agents discovered within this period, concomitant to novel biological activities displayed for known natural products, are harmonized within the present study.

scholarly journals Structure-Based Identification of Potent Natural Product Chemotypes as Cannabinoid Receptor 1 Inverse Agonists

Molecules ◽  
2018 ◽  
Vol 23 (10) ◽  
pp. 2630 ◽  
Author(s):  
Pankaj Pandey ◽  
Kuldeep Roy ◽  
Haining Liu ◽  
Guoyi Ma ◽  
Sara Pettaway ◽  
...  
Keyword(s):  
Natural Products ◽  
Natural Product ◽  
Binding Affinity ◽  
Cannabinoid Receptor ◽  
New Drugs ◽  
In Vitro Screening ◽  
Cannabinoid Receptor 1 ◽  
Cardiometabolic Disorders ◽  
Cb1 Antagonists

Natural products are an abundant source of potential drugs, and their diversity makes them a rich and viable prospective source of bioactive cannabinoid ligands. Cannabinoid receptor 1 (CB1) antagonists are clinically established and well documented as potential therapeutics for treating obesity, obesity-related cardiometabolic disorders, pain, and drug/substance abuse, but their associated CNS-mediated adverse effects hinder the development of potential new drugs and no such drug is currently on the market. This limitation amplifies the need for new agents with reduced or no CNS-mediated side effects. We are interested in the discovery of new natural product chemotypes as CB1 antagonists, which may serve as good starting points for further optimization towards the development of CB1 therapeutics. In search of new chemotypes as CB1 antagonists, we screened the in silico purchasable natural products subset of the ZINC12 database against our reported CB1 receptor model using the structure-based virtual screening (SBVS) approach. A total of 18 out of 192 top-scoring virtual hits, selected based on structural diversity and key protein–ligand interactions, were purchased and subjected to in vitro screening in competitive radioligand binding assays. The in vitro screening yielded seven compounds exhibiting >50% displacement at 10 μM concentration, and further binding affinity (Ki and IC50) and functional data revealed compound 16 as a potent and selective CB1 inverse agonist (Ki = 121 nM and EC50 = 128 nM) while three other compounds—2, 12, and 18—were potent but nonselective CB1 ligands with low micromolar binding affinity (Ki). In order to explore the structure–activity relationship for compound 16, we further purchased compounds with >80% similarity to compound 16, screened them for CB1 and CB2 activities, and found two potent compounds with sub-micromolar activities. Most importantly, these bioactive compounds represent structurally new natural product chemotypes in the area of cannabinoid research and could be considered for further structural optimization as CB1 ligands.

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