Lymphatic filariasis (LF) is a neglected tropical disease which the World Health Organization (WHO) estimates infects over 100 million people, and threatens the lives of nearly one billion in 49 countries. It is a parasitic infection caused by three species of nematode that colonize the human lymphatic system and cause permanent disability as a result of lymphedema and/or elephantiasis. Despite massive efforts by the WHO and the Global Alliance for the Elimination of LF (GAELF) to curtail the transmission of LF through mass drug administration, resistance of the parasites to antifilarial drugs is rapidly emerging as a result of both extended use and inconsistent treatment regimens. Furthermore, LF is often co-endemic with the parasitic infection onchoceriasis; these co-infections complicate the efficacy of exisiting LF treatment options.
To address failing chemotherapies, we underwent a drug discovery effort to identify and characterize novel bioactive molecules that could kill filarial worms in culture. In collaboration with Kevin Shea's lab in the Smith College Department of Chemistry, I isolated two candidate small molecules from the Mesoamerican medicinal plant Neurolaena lobata and tested their ability to kill multiple life stages of the model parasite Brugia pahangi in culture. I found that one candidate was effective at killing L3 (adolescent) parasites, while the other was completely benign. I also performed a global transcriptome analysis of the L3 parasites exposed to the bioactive compound, demonstrating broad gene-regulatory responses to treatment in a non-traditional model system.
We conjectured that the difference in toxicity observed between the two candidate compounds was due to the presence of a unique functional group in the chemical structure of the bioactive candidate. This observation inspired Dr. Kevin Shea to develop an organic chemistry lab course at Smith College that challenged students to design and test a unique organic synthesis to covalently modify that functional group with the hope of using those derivative compounds to test filarial toxicity.
Related Publications
Barnett KL, Shea KM, McGeough C, Trotta K, Williams S, Ly M, Aloisio K. Semester-Long Course-Based Research Project in Second-Semester Organic Chemistry: Synthesizing Potential Lead Compounds for the Treatment of a Neglected Tropical Disease. Journal of Chemical Education (2020)
DOI: 10.1021/acs/.jchemed.9b00685
Trotta KL. "Analysis of natural products from Neurolaena lobata as candidate antifilarial agents against the parasitic nematode Brugia pahangi" (2014). Honors Project, Smith College, Northampton, MA.
Abstract: https://scholarworks.smith.edu/theses/80
Related Presentations
Trotta KL. Analysis of natural products from Neurolaena lobata as candidate antifilarial agents against the parasitic nematode Brugia pahangi. Smith College Department of Biological Sciences Honors Defense, May 2014; Northampton, MA.
Keroack C, Trotta K. Chemical Purification, Analysis, and Organic Synthesis of Bioactive Compounds in Neurolaena lobata for the Treatment of Lymphatic Filariasis. Smith College Department of Chemistry, April 2013; Northampton, MA.