Dr. Mather studies the physiology of malaria parasites with an emphasis on mitochondrial functions, looking to identify drug targets and elucidating mechanisms of resistance.

Senior faculty mentor: Akhil Vaidya, PhD

Malaria is one of the world’s most intractable human afflictions. Campaigns against the parasitic disease have reduced the incidence by 30% in recent years until a resurgence in drug resistance and the coronavirus pandemic arrived contributing to a 12% increase in 2020. Over 240 million cases and 600,000 deaths occurred in 2020. As a member of the Center for Molecular Parasitology, under the direction of Professor Akhil Vaidya, I am involved in studies on the parasite’s energy metabolism, mitochondrial function, and the integration of the mitochondrion into cellular physiology, with an eye toward the identification and characterization of potential drug targets.

With the increasing occurrence in the field of resistance to commonly used antimalarial drugs, such new (and ideally inexpensive) drugs are urgently needed. Following the completion of the genomic sequencing projects for the human malaria parasite Plasmodium falciparum and several other malarial and apicomplexan species, many research studies have been initiated to uncover new targets for drug development. Recently, our collaborators at the Wellcome Trust Sanger Institute completed the first genome-scale phenotypic screen of the protein-coding genes in the model rodent malaria parasite P. berghei. Analysis showed that a major proportion of the genes encode products that are essential or important for growth of the parasites, The function of many of the essential proteins are unknown, since they bear no apparent similarity to previously studied proteins from mammals or other model organisms. We are working to identify novel drug targets among these essential proteins, especially those that are targeted to the mitochondrion. Using the promiscuous biotin labeling system, BioID, we are attempting to delineate the complete proteome of the parasite mitochondrion. Students are beginning to characterize selected novel but essential proteins from the mitochondrial proteome.

Work on previously identified known and potential targets also continues. The antimalarial drug atovaquone targets ubiquinol-cytochrome c oxidoreductase (bc1 complex) in the electron transport chain of the mitochondrial membrane. Our laboratory has been involved in studies to elucidate the drug's mechanism of action, the cause of the parasite’s relatively facile development of resistance by the parasite, and the mechanism behind the synergistic action of the prodrug proguanil when administered together with atovaquone. Recently, additional compounds from multiple chemical classes have been discovered that target the same complex and hold out the promise of drugs that are less susceptible to the development of resistance, less costly to manufacture and target multiple stages of the parasite’s life cycle. From among these classes, we are currently collaborating on an NIH and Medicines for Malaria Venture project to develop drugs based on the 4(1H)-quinolone scaffold (ELQ series). Pre-clinical prodrugs have been developed that show low toxicity and good antimalarial activity against multiple life cycle stages. Recently ELQ compounds that target dual sites in the bc1 complex have been developed, which promise to further reduce the ability of the parasites to evolve drug resistance. Additionally, low solubility ELQ derivatives are being investigated for use as long-lasting prophylactic treatments.

Classic drug and new candidate inhibit a mitochondrial target at nanomolar concentrations. Using parasite mitochondria prepared in the lab, the activity of the cytochrome bc1 complex is measured spectrophotometrically in the presence of inhibitors (drugs and drug candidates), and the activities are plotted versus the log of the inhibitor concentration. ELQ300 is a promising candidate effective against multiple stages of the parasite life cycle, and to which the parasites are less able to develop resistance.

The functional roles of many additional enzymes potentially involved in central metabolism, energy conversion and mitochondrial physiology, and their potential as drug targets, have been under investigation in our Laboratory and by our collaborators. These include the ATP synthase, ubiquinone-dependent oxidoreductases of the electron transport chain, TCA cycle enzymes, ADP-ATP translocators and other mitochondrial carrier proteins, enzymes of the heme biosynthesis pathway and mitochondrial ribosomes. We have shown that, due to the “minimalist metabolism” of the blood-stage Plasmodium parasite, the TCA cycle and heme biosynthesis pathways are not essential for growth and replication in the human host but are required under the very different conditions extant in the mosquito. Collaborative studies are ongoing to work out these and other details of the central metabolic pathways.

Selected publications:

“Transcriptional Changes in Plasmodium falciparum Upon Conditional Knock Down of Mitochondrial Ribosomal Proteins RSM22 and L23”
Dass S, Mather MW, Morrisey JM, Ling L, Vaidya AB, Ke H
PLoS One. 2022 Oct 6;17(10):e0274993. doi: 10.1371/journal.pone.0274993. PMID: 36201550; PMCID: PMC9536634

“Mitochondrially targeted proximity biotinylation and proteomic analysis in Plasmodium falciparum”
Lamb IM, Rios KT, Shukla A, Ahiya AI, Morrisey J, Mell JC, Lindner SE, Mather MW and Vaidya AB
PLoS One 17: e0273357 doi: 10.1371/journal.pone.0273357 (2022)

“Genetic ablation of the mitoribosome in the malaria parasite Plasmodium falciparum sensitizes it to antimalarials that target mitochondrial functions”
Ling L, Mulaka M, Munro J, Dass S, Mather MW, Riscoe MK, Llinás M, Zhou J and Ke H
The Journal of Biological Chemistry, 295: 7235-7248 doi:10.1074/jbc.RA120.012646 (2020)

“The mitochondrial ribosomal protein L13 is critical for the structural and functional integrity of the mitochondrion in Plasmodium falciparum”
Ke H, Dass S, Morrisey JM, Mather MW and Vaidya AB
The Journal of Biological Chemistry, 293: 8128-8137 (2018)

“Functional Profiling of a Plasmodium Genome Reveals an Abundance of Essential Genes”
Bushell E, Gomes, AR, Sanderson T, Anar B, Girling G, Herd C, Metcalf T, Modrzynska K, Schwach F, Martin RE, Mather MW, McFadden GI, Parts L, Rutledge GG, Vaidya AB, Wengelnik K, Rayner JC, and Billker O
Cell, 170: 260-272 (2017)

“Alkoxycarbonate Ester Prodrugs of Preclinical Drug Candidate ELQ-300 for Prophylaxis and Treatment of Malaria”
Frueh L, Li Y, Mather MW, Li Q, Pou S, Nilsen A, Winter RW, Forquer IP, Pershing AM, Xie LH, Smilkstein MJ, Caridha D, Koop DR, Campbell RF, Sciotti RJ, Kreishman-Deitrick M, Kelly JX, Vesely B, Vaidya AB, and Riscoe MK
ACS Infect Dis.;3(10):728-735 (2017)

Miley GP, Pou S, Winter R, Nilsen A, Li Y, Kelly JX, Stickles AM, Mather MW, Forquer IP, Pershing AM, White K, Shackleford D, Saunders J, Chen G, Ting LM, Kim K, Zakharov LN, Donini C, Burrows JN, Vaidya AB, Charman SA, and Riscoe MK
Antimicrobial Agents and Chemotherapy, 59: 5555-5560 (2015)

“Genetic Investigation of Tricarboxylic Acid Metabolism during the Plasmodium falciparum Life Cycle”
Ke H, Lewis IA, Morrisey JM, McLean KJ, Ganesan SM, Painter HJ, Mather MW, Jacobs-Lorena M, Llinas M, and Vaidya AB
Cell Reports, 11: 164-174 (2015)

"Quinolone-3-diarylethers: a new class of antimalarial drug"
Nilsen A, LaCrue AN, White KL, Forquer IP, Cross RM, Marfurt J, Mather MW, Delves MJ, Shackleford DM, Saenz FE, Morrisey JM, Steuten J, Mutka T, Li Y, Wirjanata G, Ryan E, Duffy S, Kelly JX, Sebayang BF, Zeeman AM, Noviyanti R, Sinden RE, Kocken CH, Price RN, Avery VM, Angulo-Barturen I, Jimenez-Diaz MB, Ferrer S, Herreros E, Sanz LM, Gamo FJ, Bathurst I, Burrows JN, Siegl P, Guy RK, Winter RW, Vaidya AB, Charman SA, Kyle DE, Manetsch R, Riscoe MK
Science Translational Medicine, 5: 177ra37 (2013)

"ATP Synthase Complex of Plasmodium falciparum: Dimeric Assembly in Mitochondrial Membranes and Resistance to Genetic Disruption"
Balabaskaran Nina P, Morrisey JM, Ganesan SM, Ke H, Pershing AM, Mather MW, and AB Vaidya
J. Biol. Chem., 286: 41312-41322 (2011)

"Hemozoin-free Plasmodium falciparum mitochondria for physiological and drug susceptibility studies"
Mather MW, Morrisey JM, and Vaidya AB
Molecular and Biochemical Parasitology, 174: 150-153 (2010)

"Highly Divergent Mitochondrial ATP Synthase Complexes in Tetrahymena thermophila"
Balabaskaran Nina P, Dudkina NV, Kane LA, van Eyk JE, Boekema EJ, Mather MW, and Vaidya AB
PLoS Biology, 8: e1000418:1-15 (2010)

"Specific role of mitochondrial electron transport in blood-stage Plasmodium falciparum"
Painter HJ, Morrisey JM, Mather MW, and Vaidya AB
Nature, 446: 88-91 (2007)

"Mitochondrial Drug Targets in Apicomplexan Parasites"
Mather MW, Henry KW, and Vaidya AB
Current Drug Targets, 8: 49-60 (2007)

"Uncovering the Molecular Mode of Action of the Antimalarial Drug Atovaquone using a Bacterial System"
Mather MW, Darrouzet E, Valkova-Valchanova M, Cooley JW, McIntosh MT, Daldal F, and Vaidya AB
The Journal of Biological Chemistry, 280: 27458 - 27465 (2005)

"Genome Sequence of the Human Malaria Parasite Plasmodium falciparum"
Gardner MJ, Hall N, Fung E, White O, Berriman M, Hyman RW, Carlton JM, Pain A, Nelson KE, Bowman S, Paulsen IT, James K, Eisen JA, Rutherford K, Salzberg SL, Craig A, Kyes S, Chan MS, Nene V, Shallom SJ, Suh B, Peterson J, Angiuoli S, Pertea M, Allen J, Selengut J, Haft D, Mather MW, Vaidya AB, Martin DM, Fairlamb AH, Fraunholz MJ, Roos DS, Ralph SA, McFadden GI, Cummings LM, Subramanian GM, Mungall C, Venter JC, Carucci DJ, Hoffman SL, Newbold C, Davis RW, Fraser CM, and Barrell B
Nature, 419: 498-511 (2002)