Chemical inhibition of apicoplast biogenesis
Katherine Amberg-Johnson (Author), Ellen Yeh (Degree supervisor), Matthew Bogyo, Karla Kirkegaard, Aaron Straight, Stanford University Department of Microbiology and Immunology
Malaria infections caused by Plasmodium spp. parasites are a serious public health problem that disproportionately affects the poorest and youngest people in the world. With 216 million infections occurring annually and growing resistance to all front-line drugs, we are in desperate need of new antimalarials with novel mechanisms-of-action. Plasmodium and other Apicomplexan parasites contain an essential, non-photosynthetic plastid organelle, called the apicoplast, which is a key antimalarial target. While the apicoplast was derived from a secondary endosymbiosis of a red alga, it is no longer photosynthetic and instead it participates in anabolic metabolism such as fatty acid, heme, iron-sulfur cluster, and isoprenoid biosynthesis. Apicoplast biogenesis depends on novel, but largely cryptic, mechanisms for the maintenance, replication, and inheritance of the organelle during parasite replication. These critical pathways present untapped opportunities to discover new parasite-specific drug targets. To discover novel factors involved in apicoplast biogenesis, we designed a chemical screen in Plasmodium falciparum to identify specific inhibitors of apicoplast biogenesis. This screen revealed the natural product antibiotic, actinonin, as a first-in-class antimalarial compound inhibiting apicoplast biogenesis. We further demonstrate that the unexpected target of actinonin in both P. falciparum and the related parasite Toxoplasma gondii is FtsH1, a AAA+ ATPase membrane metalloprotease. These findings provide an important proof-of-concept for inhibitors of apicoplast biogenesis, and lay a foundation for future studies on the role of FtsH1 in apicoplast biogenesis. Next, we provide a comparative characterization of the downstream cellular effects of the three major classes of apicoplast inhibitors in T. gondii. In contrast with P. falciparum, treatment of T. gondii with apicoplast inhibitors leads to loss of the apicoplast prior to growth defects. We find evidence that this surprising discrepancy is partially due to T. gondii's ability to scavenge host metabolites that are similar to apicoplast metabolites. Our results as whole demonstrate apicoplast biogenesis as an important and productive source of antimalarial drug targets that lead to complex downstream cellular effects that depend on the host cell environment
Thesis, Dissertation, English, 2018
[Stanford University], [Stanford, California], 2018
Stanford University
dissertations
1 online resource
1049145727
Submitted to the Department of Microbiology and Immunology