Ann Safo
MIT Department: Biological Engineering
Faculty Mentor: Prof. Jacquin Niles
Research Supervisors: Nickeisha Cuthbert, Leah Imlay
Undergraduate Institution: University of North Carolina at Chapel Hill
Hometown: Accra, Ghana
Website: LinkedIn
Biography
Ann Safo is an aspiring academic and policy advocate from Ghana whose research interests stem from lived experiences with malaria and other infectious diseases. Currently a rising senior at UNC Chapel Hill studying Biostatistics, Biology and Mathematics, Ann hopes to pursue a PhD with a focus on implementing computational and molecular tools to understand vaccine and drug efficacy of infectious diseases. In summer 2023, Ann interned with the Seydoux lab at the Johns Hopkins Medical School, where she worked on inserting a red fluorescent protein in the ifet-1 gene of C. elegans. Ann is currently interning with the Niles laboratory at MIT, where she is exploring whether delivering antioxidants alongside the antimalarial drug atovaquone can mitigate oxidative stress and subsequent mutagenesis to reduce the propensity of Plasmodium drug resistance. She has also worked with Carolina Housing for two years. Ann reads novels voraciously and loves to cook local Ghanaian dishes.
Abstract
Understanding the generation of resistance to atovaquone: The
potential role of mitochondrial reactive oxygen species
Ann Safo1, Leah Imlay2, Nickeisha Cuthbert2 and Jacquin Niles2
1Department of Biostatistics and Biology, University of North Carolina at Chapel Hill
2Department of Biological Engineering, Massachusetts Institute of Technology
Malaria kills over half a million people annually. Protecting current therapies from
resistance is vital. Atovaquone, an antimalarial that acts as an inhibitor of Cytochrome bc1
(bc1) within the mitochondrial electron transport chain (mETC) has a high propensity for
resistance via substitution mutations that weaken atovaquone’s binding to bc1. We
wondered whether this high propensity for resistance was partially due to mutagenic action
of atovaquone’s amplification of reactive oxygen species (ROS): Normally, some electrons
leak out of mETC complexes and react with oxygen to form ROS, which can cause DNA
mutations. mETC dysfunction can amplify this process; therefore, we investigated whether
antioxidants could protect against resistance. Specifically, we administered antioxidants
alongside atovaquone to detoxify ROS and assessed the effect on resistance propensity.
We performed resistance screens using three antioxidants and biological triplicates. We
also verified that antioxidants do not substantially alter atovaquone’s potency. However,
we obtained a lower than expected EC50 (concentration at which parasite viability is 50%
reduced). This result indicated that resistance experiments were conducted at 100x EC50,
instead of 10x as intended. Future assays will investigate our hypothesis under ideal
conditions. If our hypothesis is supported, antioxidants may provide an inexpensive means
of safeguarding antimalarials against resistance.
