Advancements in the Bioproduction of Natural Product Drugs

Compared to typical synthetic small molecule libraries, natural product libraries are rich in biologically active compounds covering a broader chemical space. They often possess higher molecular weights, greater skeletal diversity, and structural complexity. Drug molecules derived from natural products and important semisynthetic drug precursors include steroids, polyketides and fatty acids, non-ribosomal peptides, alkaloids, and terpenes, among others. The synthesis of natural products within organisms is usually geared towards specific biological functions, such as participating in regulating endogenous defense mechanisms and competing with other organisms for survival. This also explains the high relevance of natural products in the treatment of infectious diseases and cancer.

However, the contribution of natural products to drug development also faces challenges, such as the effective exploration of novel active molecules, isolation and characterization of biologically active trace natural products, and generation of natural product analogs for exploring structure-activity relationships. Additionally, there are many bottlenecks in industrial production of complex natural drugs, mainly due to the low abundance of most medicinal natural products in nature and the immense difficulty in total chemical synthesis. In recent years, with improvements in analytical tools, continuous upgrades in genome mining and engineering strategies, and progress in microbial fermentation, these challenges are gradually being addressed, leading to the industrial synthesis of increasingly complex natural products.

FDA-approved Natural Product Drugs

Among the newly approved drugs by the FDA, those based on natural products or semisynthetic derivatives thereof constitute a significant portion.

Table 1 Summary of FDA-approved natural product drugs and semisynthetic drugs.

In the past decade, there are 28 newly approved drugs derived from natural products and their semisynthetic derivatives, accounting for 8.5% of the total number of newly approved drugs by the FDA (331 drugs). Among them, there are 9 instances of new molecular entities derived from natural products with unchanged structures, mainly derived from human and animal steroids and peptides, including drugs such as cholic acid for improving bile acid synthesis disorders, deoxycholic acid for fat cell destruction, taurursodiol for treating amyotrophic lateral sclerosis, prasterone for treating menopausal symptoms, estetrol as a contraceptive, and angiotensin II for blood pressure regulation. Another portion comes from plant and microbial secondary metabolites, including polyketides and non-ribosomal peptides, such as tapinarof for treating psoriasis, cannabidiol for treating epilepsy, and trabectedin as an antitumor drug. There are 19 instances of new molecular entities synthesized semi-synthetically from precursors derived from natural products, including non-ribosomal peptides such as the antifungal drug rezafungin, terpenes such as the antibacterial drug lefamulin, and polyketides such as the antiparasitic drug moxidectin.

Additionally, some FDA-approved drugs have made significant progress in biosynthesis research in the past decade. They have not only gradually improved in terms of understanding biosynthetic pathways, including weight-loss drug orlistat, anticancer drugs etoposide, vinblastine, vincristine, colchicine for gout treatment, and analgesic drugs morphine and codeine, but also made important progress in the total biosynthesis of microbial engineered natural products, such as the anticholinergic drug scopolamine, anticancer drug paclitaxel, vinblastine, and vitamin B12.

Examples of Natural Product Drugs

• Steroidal Natural Products

Taurursodiol (TURSO), also known as ursodoxicoltaurine or tauroursodeoxycholic acid (TUDCA), is the active ingredient in the FDA-approved drug Relyvrio, which is used to treat amyotrophic lateral sclerosis (ALS). TUDCA is a highly hydrophilic bile acid that reduces cholesterol absorption in the small intestine, thereby lowering both dietary cholesterol intake and endogenous cholesterol levels in the body. Additionally, TUDCA exhibits anti-apoptotic and endoplasmic reticulum stress inhibitory effects and is used in some countries to treat gallstones due to its efficacy and safety.

• Non-ribosomal Peptide Natural Products

Trabectedin, also known as ecteinascidin 743 (ET-743), is the first marine-derived novel anti-soft tissue tumor drug isolated in 1984 from the Ecteinascidia turbinata. The unique mechanism of action of ET-743 stems from its alkylamino portion, which can be converted into electrophilic iminium ions that alkylate DNA, interfering with cell division, gene transcription processes, and DNA repair mechanisms. It has been approved in several countries for the treatment of advanced soft tissue sarcomas. In 2015, the FDA approved the drug Yondelis, which contains ET-743 as the active ingredient, for the treatment of advanced soft tissue sarcomas and ovarian cancer.

• Lignan Natural Products

Etoposide, approved by the FDA in 1983, is a chemotherapy drug used to treat various types of cancer, such as testicular and small cell lung cancer. Etoposide forms a complex with topoisomerase II and DNA, inducing DNA double-strand breaks and inhibiting the binding of topoisomerase II to repair DNA, thereby inhibiting DNA synthesis and causing cell death. Etoposide is a semi-synthetic derivative of podophyllotoxin, which belongs to the lignan class of natural products and is isolated from the medicinal plant Podophyllum hexandrum.

• Alkaloid Natural Products

Vinblastine, approved by the FDA in the 1960s, is an effective anticancer drug that binds to tubulin protein, inhibiting microtubule assembly. It is commonly used in combination with other drugs to treat various types of cancer, including Hodgkin's lymphoma, non-small cell lung cancer, bladder cancer, brain cancer, melanoma, and testicular cancer. Vincristine, also approved during the same period, is used to treat acute leukemia, malignant lymphoma, and acute myeloid leukemia. Both vinblastine and vincristine are dimers of two monoterpenoid indole alkaloids isolated from Catharanthus roseus.

• Terpene Natural Products

Lefamulin is a semi-synthetic antibiotic derived from pleuromutilin, approved by the FDA in 2019 for the treatment of adult bacterial pneumonia. Lefamulin binds to the peptidyl transferase center of bacterial 50S ribosomal subunit, thereby inhibiting bacterial protein synthesis. Pleuromutilin, the semi-synthetic precursor of lefamulin, belongs to the diterpene class of natural products, first isolated from fungi of the genera Pleurotus in 1951. The main characteristic of pleuromutilin is a tricyclic skeleton resembling a spiro[4.4]nonane, composed of five-, six-, and eight-membered rings. Researchers have elucidated the cyclization mechanism of the pleuromutilin tricyclic skeleton, finding that during the proton-dependent cyclization process of geranylgeranyl diphosphate (GGPP), a II-type terpene synthase catalyzes ring contraction to form a 5/6 bicyclic skeleton. Then, a I-type sesquiterpene synthase domain catalyzes dephosphorylation to form the eight-membered ring while capturing a molecule of water, introducing the first hydroxyl group at C14 of the tricyclic skeleton.

Prospects

Natural products encompass a diverse range of structural types, including steroids, polyketides, non-ribosomal peptides, terpenes, alkaloids, and more, and play crucial roles as lead compounds in treating human diseases. The development of bioinformatics has greatly accelerated the discovery of new natural product drugs, especially through the utilization of abundant genomic data resources to determine gene cluster boundaries and biosynthetic pathways. Additionally, genome mining has led to the discovery of many structurally novel natural products that were previously challenging to identify.

Especially in recent years, with the spread of antibiotic resistance, the efficacy of medical antibiotics is gradually declining, making the discovery of fundamentally new antibiotics imminent. Modern antibiotic discovery strategies have shifted towards multidisciplinary and multi-omics (such as metabolomics, proteomics, transcriptomics, genomics, etc.) combined application strategies, integrating molecular biology and synthetic biology methods to mine genomes and activate silent gene clusters to obtain new antibiotics, as well as adopting chemical optimization strategies to produce antibiotics with excellent activity. The combined application of these modern natural product research methods has greatly accelerated the speed of novel drug discovery.