In a quest for new weapons against deadly bacteria, scientists have turned to the intricate chemistry of nature, discovering potent compounds inspired by ancient evolutionary designs.
Imagine a vast library where instead of books, the shelves are filled with millions of unique chemical compounds, each with the potential to become a life-saving drug. This is the concept of a screening library in drug discovery. Yet, despite technological advances, finding new effective drugs has become increasingly difficult. Facing this challenge, scientists are returning to nature's time-tested molecular blueprints—natural product scaffolds—to build better libraries and discover the medicines of tomorrow.
Natural products (NPs) are complex chemical compounds produced by living organisms—plants, microbes, and marine creatures. Having evolved over millennia to interact with biological systems, they possess unmatched biological relevance that synthetic compounds struggle to match 1 5 .
Studies have revealed that natural products tend to have greater three-dimensional complexity than synthetic molecules, with more chiral centers and sp³-hybridized carbon atoms. This structural richness correlates strongly with clinical success 5 .
Approximately 56% of all drugs approved between 1981 and 2019 were either natural products, their direct derivatives, or synthetic compounds containing active pharmacophores from secondary metabolites .
Despite their promise, working directly with natural products presents challenges: difficulty in isolation, structural complexity that hinders synthesis, and potential toxicity. This has led scientists to a powerful compromise—extracting the core "scaffolds" of natural products and using them to generate diverse screening libraries that capture nature's wisdom while enabling modern drug optimization 9 .
of drugs approved 1981-2019 are natural product-derived
The term "privileged scaffolds" refers to core structural frameworks of natural products that can be modified to produce multiple bioactive compounds 1 5 . Instead of attempting to synthesize entirely new chemical entities from scratch, researchers use these proven natural scaffolds as foundations for creating focused libraries.
The largest class of natural products, representing approximately 60% of NP diversity, with structures ranging from simple monoterpenes to complex meroterpenoids exhibiting antiviral, anticancer, and cytotoxic activities 5 .
Despite being the smallest NP class, alkaloids include commercially important drugs like morphine, vincristine, and quinine, with diverse biological activities 5 .
A pharmaceutically valuable class with annual sales totaling approximately $10 billion, including important antibiotic and anticancer agents 5 .
Diverse plant-derived compounds that have inspired potent drug candidates, such as DDP-4 inhibitors for diabetes treatment 5 .
The strategic value of this approach lies in starting with biologically pre-validated platforms—these molecular frameworks have already been "tested" through evolution for specific biological functions, giving them a head start in the drug discovery race 1 .
The promise of natural product-inspired libraries was powerfully demonstrated in a 2021 study published in Scientific Reports, where researchers discovered novel compounds capable of inhibiting Clostridioides difficile, a dangerous gastrointestinal pathogen 8 .
They screened 5,000 natural product-inspired synthetic compounds from the AnalytiCon NATx library against C. difficile at a concentration of 3 μM 8 .
From initial screening, 34 compounds showed inhibitory activity. These were "cherry-picked" and rescreened, confirming 10 true hits 8 .
Minimum inhibitory concentration (MIC) assays were performed against a panel of 16 hypervirulent and clinically toxigenic C. difficile strains 8 .
Compounds were tested against beneficial gut bacteria species to ensure they wouldn't disrupt the natural microbiome 8 .
Cytotoxicity was assessed using human colorectal adenocarcinoma (Caco-2) cells to ensure safety for human cells 8 .
The screening identified three particularly promising compounds with potent activity against C. difficile and favorable selectivity profiles.
| Compound ID | MIC90 (μg/ml) | Comparative Activity |
|---|---|---|
| NAT18-355531 | 1 | Comparable to vancomycin |
| NAT18-355768 | 1 | Comparable to vancomycin |
| NAT13-338148 | 2 | Onefold less than vancomycin |
| Vancomycin | 1 | Standard-of-care drug |
| Compound | Effect on Gut Microbiota |
|---|---|
| NAT13-338148 | No inhibition of beneficial Bacteroides and Bifidobacterium species at >8 μg/ml |
| NAT18-355531 | Inhibited tested species at 4 μg/ml |
| NAT18-355768 | Inhibited tested species at 4 μg/ml |
| Vancomycin | Inhibited Gram-positive Bifidobacterial members at very low concentrations |
| Fidaxomicin | Inhibited Gram-positive Bifidobacterial members at very low concentrations |
| Compound | Caco-2 Cell Viability at 16 μg/ml |
|---|---|
| NAT13-338148 | Nontoxic |
| NAT18-355531 | Nontoxic |
| NAT18-355768 | Nontoxic |
The research successfully identified novel natural product-inspired scaffolds, particularly NAT13-338148, NAT18-355531, and NAT18-355768, that demonstrated potent anticlostridial activity, favorable selectivity over beneficial gut bacteria, and minimal cytotoxicity 8 . This trifecta of properties represents a significant advancement in antibiotic discovery, addressing the critical need for drugs that can target pathogens without disrupting the delicate balance of the gut microbiome.
| Tool/Resource | Function | Example/Application |
|---|---|---|
| Natural Product-Inspired Libraries | Pre-curated collections for screening | AnalytiCon NATx library 8 |
| Specialized Compound Libraries | Targeted screening approaches | Covalent Inhibitors Library, 3D-Pharmacophore Library 7 |
| Advanced Analytical Technologies | Isolation and characterization | HPLC-HRMS, NMR profiling 6 |
| Bioinformatics & Databases | In silico screening and design | Global Natural Products Social Molecular Networking 6 |
| Biological Resources | Source of novel natural products | Brazilian biodiversity |
Despite historical successes, natural product research faces ongoing challenges including technical barriers in isolation and characterization, supply chain complexities, and regulatory considerations regarding biodiversity access and benefit-sharing under frameworks like the Nagoya Protocol 6 .
NPs remain vital to drug discovery, demonstrating adaptability in tackling complex medical challenges.
From ancient remedies to modern laboratories, natural product scaffolds serve as bridges between nature's evolutionary wisdom and human scientific ingenuity—proving that sometimes, the best solutions come from working with, rather than against, nature's designs.