Faster workflows boost drug discovery in natural product-based screening

Plants, marine invertebrates, and microbes have been a major source of novel drugs against cancer, viruses, and fungal diseases. New isolation methods are making it faster and easier to discover these natural products.

To encourage ongoing drug development from natural products, a collaboration of government and contractor scientists demonstrated accelerated methods of identifying natural compounds that have activity against bacteria and fungi – an early step in drug discovery.

More than half of new antibacterial medicines entering the clinic from 1981 to 2019 came from natural products or their derivatives, the scientists reported. But going from a natural product to a potential medicine is a hit-or-miss proposition, typically requiring repeated tests to see if a natural compound shows activity against a microbe.

Collaborator Chris Thornburg of the Frederick National Laboratory cited new methods that have compressed the timeline for these exploratory experiments. To get an initial positive signal from these tests, “We can do that in less than two months... It used to take up to a year or more.”

As a demonstration, a research group led by the National Institute of Allergy and Infectious Diseases and the National Cancer Institute started with 326,656 natural product fractions from the NCI’s Natural Products Extract Repository, one of the world’s largest such collections.

Natural product fractions, in which the crude extracts of the original source material have been partially purified, are amenable to high-throughput screening because they reduce many of the problems associated with screening intact extracts, such as solubility issues and assay-interfering components. The NCI fraction library used for the NIAID screen included 3,454 plant, 2,027 marine, 104 fungal, and 94 algal samples collected worldwide.

The researchers tested these fractions against four microbial pathogens, S. aureus, two strains of E. coli, and C. albicans. Together, these represent some of the most common microbial pathogens that threaten human health. The tests identified more than 3,000 fractions with antifungal or antiviral activity against at least one of these microbes. Most of this activity did not appear when testing the crude extracts simultaneously.

In the next step, the scientists chose 75 representative fractions and separated each one into 22 further purified subfractions. Additional testing revealed two previously unknown antimicrobial molecules, one antifungal and the other antiviral.

“The proof-of-concept study identified many different chemotypes, several of which have not previously been reported to have antimicrobial activity,” the scientists reported in the journal ACS Infectious Diseases. “The results show that there remain many unidentified antibiotic compounds from nature.”

The researchers demonstrated a fast and efficient workflow for “modern bioassay-guided isolation of biologically active compounds” from natural products but left further drug discovery and development work open to any other government, academic, or commercial group that may want to pursue the leads that resulted from this project. Data from the project is available and adds a free resource for follow-up studies.

In addition to the need for new drugs for existing diseases, antibiotic resistance is a growing concern. Antibiotic-resistant microbes cause an estimated 35,000 deaths a year in the United States. But recent drug approvals for antibiotics have been slower than desired. This is especially important for cancer patients who are often immunocompromised.

Scarcity is another issue. Recent shortages of drugs such as Bicillin L-A for such diseases as syphilis and amoxicillin for infections such as strep throat have raised additional awareness of the need fpr antimicrobial medicines.