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Michael Mather

Michael Mather, PhD

Research Assistant Professor


Department: Microbiology & Immunology

Education

  • PhD - University of Illinois, 1984

Dr. Mather is a research assistant professor in the Department of Microbiology and Immunology at Drexel University College of Medicine.

Research Overview

Research interests: Physiology of malaria parasites, especially mitochondrial functions and energy metabolism

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. Despite intensive campaigns against the parasitic disease, an estimated 220 million cases still occur each year, and the situation may again be worsening due, in large part, to the 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 mitochondrial function and the integration of the mitochondrion into cellular physiology, with an eye toward the identification and characterization of potential drug targets.

Following the completion of the recent 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. With the increasing occurrence in the field of resistance to commonly used antimalarial drugs, such new (and ideally inexpensive) drugs are urgently needed.

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 and less costly to manufacture. From among these classes, we are currently collaborating on a Medicines for Malaria Venture project to develop drug leads based on the 4(1H)-quinolone scaffold.

The functional roles of many additional enzymes potentially involved in central metabolism, energy conversion and mitochondrial physiology, and their potential as drug targets, are under investigation in our laboratory. These include the ATP synthase, ubiquinone-dependent oxidoreductases of the electron transport chain, TCA cycle enzymes, ADP-ATP translocators, enzymes of the heme biosynthesis pathway and proton-pumping pyrophosphatases. Important results have recently emerged from work on the TCA cycle pathway. Due to the "minimalist metabolism" of the blood-stage Plasmodium parasite, the cycle is not essential for growth and replication in the human host, although it may be required under the very different conditions extant in the mosquito. We have been able to generate genomic knockouts of the genes encoding six of the eight TCA enzymes, clearly establishing that they are not essential for the growth of the blood stage of the parasite. Only the remaining two TCA enzymes proved recalcitrant to disruption and thus are required for growth, making them potential drug targets. The nature of the essential function of these two enzymes, when the TCA cycle as a whole is dispensable, is an important question under investigation. Another key question is the source of acetyl-CoA in the mitochondrion, since it lacks a pyruvate dehydrogenase complex. Collaborative studies are ongoing to work out these and other details of the metabolic pathways and any alternatives that may come into play when specific enzymes are knocked out.

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 distant relative 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. One Tetrahymena b subunit candidate has a possible homologue in apicomplexan species, which we are investigating. 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 and define its composition and function.

Publications

Selected publications:

"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)

"Yeast dihydroorotate dehydrogenase as a new selectable marker for Plasmodium falciparum transfection"
Ganesan SM, Morrisey JM, Ke H, Painter HJ, Laroiya K, Phillips MA, Rathod PK, Mather MW, and Vaidya AB
Molecular and Biochemical Parasitology, 177: 29-34 (2010)

"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)

"Branched Tricarboxylic Acid Metabolism in Plasmodium falciparum"
Olszewski KL, Mather MW, Morrisey JM, Garcia BA, Vaidya AB, Rabinowitz JD, and Llinas M
Nature, 466: 774-778 (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)

"A Post-Genomic View of the Mitochondrion in Malaria Parasites"
Vaidya AB and Mather MW
Current Topics in Microbiology and Immunology, 295: 233 - 250 (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)

"Atovaquone Resistance in Malaria Parasites"
Vaidya AB and Mather MW
Drug Resistance Updates, 3: 282-287 (2000)


Contact Information


Research Office

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