For a better experience, click the Compatibility Mode icon above to turn off Compatibility Mode, which is only for viewing older websites.

Michael Mather

Michael Mather, PhD

Research Assistant Professor


Department: Microbiology & Immunology

Education

  • PhD - University of Illinois, 1984

Michael Mather, PhD, is a research assistant professor in the Department of Microbiology & Immunology at Drexel University College of Medicine.

Research Overview

Senior faculty mentor: Akhil Vaidya, PhD

Research Interests

Physiology of malaria parasites, especially mitochondrial functions and energy metabolism

Research

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, but nearly 200 million cases still occur each year, and the situation remains perilous, due to the continuing emergence and spread of drug resistant parasites. 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 functions 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 will be working to identify novel drug targets among these essential proteins, especially those that may be targeted to the mitochondrion. Using the promiscuous biotin labeling system, BioID, we are attempting to delineate the complete proteome of the parasite mitochondrion.

Work on previously identified known and potential targets also continues. The antimalarial drug atovaquone targets ubiquinol-cytochrome c oxidoreductase in the electron transport chain of the mitochondrial membrane.  Our laboratory has been involved in studies to elucidate the mechanism of action of the drug, the cause of the 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 a 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 stages of the life cycle.

Classic drug and new candidate inhibit a mitochondrial target at nanomolar concentrations

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. 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 pathway is not essential for growth and replication in the human host, although it is required under the very different conditions extant in the mosquito. We generated genomic knockouts of the genes encoding most of the TCA enzymes, clearly establishing that they are not essential for the growth of the blood stage of the parasite. One TCA enzyme, fumarate hydratase, however, remains essential for blood-stage growth, and thus a potential drug target. The nature of the essential functionality of this enzyme, when the TCA cycle as a whole is dispensable, is an important question under investigation. Collaborative studies are ongoing to work out these and other details of the central metabolic pathways.

The malarial ATP synthase also appears to be unusual, since no genes for the critical a and b subunits that are required for energy coupling could be identified in the genome. Its activity in the blood stage is also very low, suggesting that oxidative phosphorylation, like the TCA cycle, does not play a major role in this stage. We recently studied the ATP synthase in the ciliate Tetrahymena thermophila, a related organism from which mitochondria are more easily prepared in quantity. Structural EM and proteomics studies revealed a ciliate ATP synthase that indeed has many novel features, as well as revealing candidate protein subunits that may serve as divergent a and b subunits. We then investigated the P. falciparum ATP synthase, applying molecular genetic, biochemical and immunological methods. Despite the low level of the enzyme in mitochondria from the blood stage parasites, we were able to show that it is present as a large, probably dimeric, complex, implying the presence of additional novel/divergent subunits, as in Tetrahymena. We further demonstrated by gene knockout techniques that the ATP synthase complex is probably essential, again, despite its low concentration and the apparent unimportance of oxidative phosphorylation in blood stage malaria parasites. Further studies are ongoing in an effort to verify the essential nature of the ATP synthase, define its composition and function, and test our hypothesis that the synthase is the target of the synergistic action of proguanil in atovaquone-proguanil formulations.

Publications

Selected publications:

“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)

“ELQ-300 prodrugs for enhanced delivery and single-dose cure of malaria”
Galen P. Miley, Sovitj Pou, Rolf Winter, Aaron Nilsen, Yuexin Li, Jane X. Kelly, Allison M. Stickles, Michael W. Mather, Isaac P. Forquer, April M. Pershing, Karen White, David Shackleford, Jessica Saunders, Gong Chen, Li-Min Ting, Kami Kim, Lev N. Zakharov, Cristina Donini, Jeremy N. Burrows, Akhil B. Vaidya, Susan A. Charman, Michael K. Riscoe
ACS Infectious Diseases, 3: 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)

"Mitochondria in malaria and related parasites: ancient, diverse and streamlined"
Mather MW and Vaidya AB
Journal of Bioenergetics and Biomembranes, 40: 425 - 433 (2008)

"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)


Contact Information


Research Office

Department of Microbiology & Immunology
2900 W. Queen Lane
Philadelphia, PA 19129
Phone: 215.991.8256
Fax: 215.848.2271