Integration of Natural Products and High-Content Phenotypic Screening

Diagram of molecles
Novel natural products discovered from our collection

The intricate chemical structures of natural products have the advantage of optimization over evolutionary time scales for interaction with biological systems at sub-µM potency. A proven drug-screening paradigm for natural product collections has been the use of cell-based phenotypic screens, such as cytotoxicity, for selection of molecules with reasonable physiochemical properties. The development of high-content phenotypic screens, such as image-based and reporter-based, has opened up tremendous possibilities for the study of natural products. We have integrated our natural products fraction library, which consists of ~6,500 natural product fractions, with a number of high-content phenotypic screens taking place in the UTSW high-throughput screening facility.

Non-Small Cell Lung Cancer

One area of primary interest is identifying molecules with selective activity against non-small cell lung cancer (NSCLC), the most prevalent form of lung cancer. Working with John Minna, M.D. Professor in the Hamon Center for Therapeutic Oncology, Michael A. White, Ph.D., Professor of Cell Biology, and Michael Roth, Ph.D., Professor of Biochemistry, we are screening our natural products fraction library against a panel of 30 NSCLC cell lines to identify selective toxins. This project is part of the Cancer Target Discovery and Development (CTD2) network.

Discovery of selective natural product toxins using phenotypic screens

Gram-Negative Pathogens

Another therapeutic interest is discovering antibiotics that work against Gram-negative pathogens. Over the past decade a great deal of attention has been placed on the emerging resistance in Gram-positive bacteria, such as methacillin-resistant Staphylococcus aureus. The need for new agents is most pressing in hospital-acquired infections, where Gram-negative isolates of the genera Klebsiella, Acinetobacter, and Pseudomonas are resistant to an increasingly high number of our antibiotic arsenal.

We set up a screen to identify natural products that had bactericidal/bacteriostatic activity against Pseudomonas aeruginosa and Burkholderia cenocepacia, ultimately leading to mangrolide A, a macrolide antibiotic with potent and selective antibiotic activity against Gram-negative pathogens. In collaboration with Ilmin Kwon, Ph.D., a postdoctoral researcher in the lab of Steven McKnight, Ph.D., Chair of Biochemistry, we have determined mangrolide A's mechanism of action. We are currently collaborating with the lab of Jef De Brabander, Ph.D., Professor of Biochemistry, on the total synthesis and structure-activity relationship studies and the UTSW Pharmacology core on ADME/Tox studies to further develop mangrolide A and analogs for treatment of Gram-negative bacterial infections.

Discovery of mangrolide A as a Gram-negative selective antibiotic that causes amino acid misincorporation