Plant-derived drugs and Drug Discovery

Natural Products as Drugs

• Natural products are a vital source of drugs.
• In medicinal chemistry, a natural product is a chemical compound or substance made by a living organism.
• Natural products are secondary metabolites, not strictly essential for survival.
• A broader definition includes mixtures of natural products like botanical extracts and proteins like defense peptides and enzymes.
• A global survey shows that from 1981–2019, 1,881 drugs were approved for clinical use.
• Antibiotics and antimicrobials are obvious examples of nature's role, mainly from NPs made by bacteria and fungi.
• Plants also generate useful drugs, making a huge array of secondary metabolites for defense.

Plants as Chemical Factories

• Pacific yew trees contain paclitaxel.
• Interest in the tree for medicinal properties began in the 1960s.
• Scientists at the National Cancer Institute (NCI) screened natural compounds from plants to combat cancer.
• In 1962, paclitaxel, known as Taxol, was isolated from the bark of the Pacific yew tree.
• Paclitaxel can inhibit cancer cell division and is a candidate for cancer treatment.
• Taxol blocks mitosis by stopping microtubules from depolymerizing.
• It is mainly used against breast, ovarian, and cervical cancers and many other cancers, too.
• Before surgery, it slows aggressive cancers and reduces the chance of metastasis and to shrink tumors.
• After surgery, it reduces the risk of cancer returning, and generics are available.
• The global market growth for Taxol is expected to rise from $4.5 Bn in 2021 to $11.2 Bn in 2030.
• In the 1940s, Dr. Percy Julian and his team investigated converting stigmasterol from soybeans into steroid hormones.
• They accidentally discovered stigmasterol could be converted into testosterone and other important hormones.
• Tu Youyou discovered artemisinin from sweet wormwood.
• Artemisinin is a Chinese remedy from AD 340 used for intermittent fevers.

Ethnopharmacology

• Ethnopharmacology is the scientific study of substances used medicinally by different ethnic or cultural groups, especially traditional remedies.
• Studying traditional medicines may help create a new discovery pipeline for new drugs to treat bacterial infections.
• Screening environmental microbes for antibiotic compounds often leads to rediscovering known molecules, and screening random compound libraries isn't effective.
• Examining traditional or historical medicine may provide a more focused approach.
• An early medieval infection treatment is Bald's eyesalve.
• Bald's eyesalve contains garlic, onion, wine, and bile.
• Bald’s eyesalve works by disrupting biofilms.

Biofilms

• To analyze biofilms, bacteria that form biofilms is chosen then inoculated in a nutrient medium.
• Grow in a static environment for 24–48 hours and analyze the biofilm using staining or microscopy.
• Bald's eyesalve kills staphylococcus aureus in biofilms.
• More than one active compound is needed to kill biofilms.
• Allicin explains most bacterial killing in planktonic culture and is a promising candidate, being volatile and an irritant.
• High rates of carbapenem-resistant Acinetobacter lead to over 8,500 estimated cases in hospitalized patients in 2017.
• This resulted in 700 estimated deaths and approximately $281M in estimated healthcare costs in 2017.
• 550,000 estimated cases of drug-resistant Neisseria gonorrhoeae infections occur each year.
• Annually, 1.14M total new infections occur which cost approximately $133.4M in lifetime direct medical costs.
• 5.3M people are expected to have diabetes worldwide by 2025.
• 10% of diabetic patients will get an infected foot/leg ulcer, with 2.7M people in Europe having venous leg ulcers.
• 3.7M people in Europe have pressure sores which costs the NHS approximately £3.2Bn annually.

Considerations for mixtures that kill bacterial biofilms

• A mixture must have a defined, chemically characterized mixture, reproducible manufacturing, and defined effects.
• It must also be safe and not have any adverse effects.
• Does it work in vivo?
• Does it work in an animal model and/or humans?
• A pathway for safety testing includes cell lines, ex vivo organs, live animal models, and human phase 0 trials.
• Bald's eyesalve in an ex vivo model of irritation can be tested with a Bovine Corneal Opacity & Permeability Assay.
• Bald's eyesalve can be tested in a live animal for wound closure in mice.

Human Safety Trial Results

• 109 participants aged 18-77 were recruited for a human safety trial.
• Participants were healthy with no known allergies or risk factors for a serious reaction in phase 0/1.
• They wore a plaster impregnated with 100µl of the eyesalve for 48 hours.
• They were followed up to ask if they had any adverse events (AEs: medical occurrences with the patch test, but not necessarily caused by it).
• AEs can be mild (discomfort, itching) or more serious (allergic reaction -> anaphylaxis).
• Two participants were lost to follow-up, and one withdrew due to the garlic smell.
• 13.2% experienced AEs related to the eyesalve with all showing mild symptoms like redness and itching.
• Only 1 person reported broken skin.
• 6.6% experienced AE related to plaster adhesive.
• 80.2% experienced no AEs.

Final Points

• Natural products are important sources of drugs.
• Natural products could help discover new treatments for antibiotic-resistant infections like biofilm infections of chronic wounds.
• Mixtures of natural products can be more effective than single molecules in killing bacterial biofilms.
• Studying traditional or historical medicines could help find NP mixtures worth exploring in the lab.
• Research is a long process to move from a mixture in the lab to a formulation for clinical trials and involves thorough safety testing.

Explore the role of plants as 'chemical factories' and the significance of secondary metabolites, Paclitaxel's discovery and its biological activity, the impact of synthetic modification on natural products, and what makes a botanical product different from a natural product. Also covered anti-biofilm treatments, the suitability of volatile compounds as drug candidates in the context of chronic wound biofilm infections.