Akhil Vaidya Professor, Microbiology and Immunology Director, Center for Molecular Parasitology Ph.D., 1972, University of Bombay, India 2900 Queen Lane Philadelphia, PA 19129 Tel: 215-991-8557 Fax: 215-848-2271 Email: avaidya@drexelmed.edu

Research Staff: Joanne Morrisey, Michael Mather, Ph.D., Heather Painter, Ph.D., Kamal Laroiya
Graduate Students: Hangjun Ke, Suresh Ganesan, Praveen Balabaskaran

Keywords:

Malaria, mitochondrial DNA, antimalarial drugs, DNA microarrays, genomics, bioinformatics, Ayurvedic medicine, mechanisms of drug action and resistance, bioenergetics, proton pumps, treatment for severe malaria

Research Interests

Man’s encounter with malaria over the evolutionary time has left many footprints on the human genome: persistence of certain harmful genetic traits in human populations is favored because they provide protection against severe malaria.  The problem of malaria remains unabated in much of the world with 40% of the human beings at risk of being infected with malaria parasites.  Our laboratory focuses on understanding basic molecular functioning of malaria parasites with a view to develop new antimalarial drugs.  A number of different research projects are underway in our laboratory supported by research grants from the National Institutes of Health, USA.

In 1989, our laboratory discovered that the mitochondrial genome of malaria parasites consisted of a very unusual DNA molecule of 6 kilobase in length. This DNA encodes only 3 proteins as well as very unusually organized ribosomal RNA genes in pieces. The mitochondrion of malaria parasites is quite distinct from its counterpart in humans and provides a validated target for antimalarial drug action.

We have shown that a new antimalarial drug, atovaquone, preferentially interferes with mitochondrial electron transport in malaria parasites. Resistance to this drug arises quickly, and is mediated by subtle changes within the mitochondrially encoded cytochrome b protein. Visualization of these changes has revealed atovaquone-binding domain within the parasite bc1 complex. Investigations using a bacterial system to resemble malarial cytochrome b revealed subtle molecular interactions that underlie selective activity of the atovaquone class of antimalarial drugs as well as the mechanisms by which resistance against these drugs arise.

A model describing the generation of mitochondrial membrane potential in P. falciparum.  a.  The usual mitochondrial electron transport-dependent membrane potential generation involves reduction of CoQ (Q→QH2) by various dehydrogenases, of which DHOD appears to be the essential enzyme.  Re-oxidation of QH2 by the cytochrome bc1 complex and subsequent electron transfer to cytochrome c and oxygen results in proton translocation and generation of electropotential across the inner membrane with the matrix being negatively charged.  Atovaquone, by inhibiting the cytochrome bc1 complex, will prevent this mode of electropotential generation and will also prevent re-oxidation of QH2.  b.  Another route for electropotential generation could be through adenine nucleotide carrier (ANC) in conjunction with the F1 sector of the F-ATPase and the mitochondrial phosphate carrier.  Import of ATP4- in exchange for ADP3- by ANC would be electrogenic, producing a net negative charge in the matrix.  The imported ATP would be hydrolyzed to ADP and inorganic phosphate (Pi) by the F1 ATPase, ADP will be exchanged for ATP from the intermembrane space by the ANC, and Pi- will be exchanged for OH- by the mitochondrial phosphate carrier (an elecrtoneutral exchange).  When membrane potential generation through the electron transport chain is inhibited, this alternate path can provide the necessary membrane potential.  Proguanil may interfere with any one of the three components of this alternate system as indicated; in the presence of atovaquone or other electron transport inhibitors, the generation of electropotential would be hypersensitive to proguanil. (from Painter et al. Nature 446:88-91, 2007)

Selected Research Publications

1. Povinelli, L., Fox, B., Monson, T.,Green, M., Parise, M., Morrisey, J. M., and A. B. Vaidya.  P. vivax Malaria in Spite of Atovaquone/Proguanil (MalaroneTM) Prophylaxis.  J. Travel Med., 10: 353-355, 2003.
   
   
2. Kaiser, K., Camargo, N., Coppens, I., Morrisey, J. M., Vaidya, A. B., and S. H. I.  Kappe.  A member of a conserved Plasmodium protein family with membrane-attack complex/perforin (MACPF)-like domains localizes to the micronemes of sporozoites.  Mol. Biochem. Parasitol., 133: 15-26, 2004.
   
   
3. Vaidya, A. B.  Mitochondrial and plastid functions as antimalarial drug targets.  Current Drug Targets --Infectious Disorders, 4: 11-23, 2004.
   
   
4. Vaidya, A. B.  Malaria parasites deck the holes in erythrocytes.  Blood 104: 3844, 2004.
   
   
5. Vaidya, A. B. and M. W. Mather.  A post-genomic view of the mitochondrion in malaria parasites.  Current Topics in Microbiology and Immunology, 293: 233-250, 2005.
   
   
6. Vaidya, A. B.  The Mitochondrion In: Molecular Approaches to Malaria (Sherman, I. W., editor) pp 234-252, ASM Press, Washington, D.C., 2005.
   
   
7. Mather, M. W., Darrouzet, E., Valkova-Valchanova, M., Cooley, J. W., McIntosh, M. T., Daldal, F., and A. B. Vaidya.  Uncovering the molecular mode of action of the antimalarial drug atovaquone using a bacterial system.  J. Biol. Chem., 280: 27458-27465, 2005.
   
   
8. Shi, Q., Cernetich, A., Daly, T. M., Galvan, G., Vaidya, A. B., Bergman, L. W., and J. M. Burns, Jr.  Alteration in host cell tropism limits the efficacy of immunization with a surface protein of malaria merozoites.  Infect. Immun., 73: 6363-6371, 2005.
   
   
9. Talwalkar, S. S., Vaidya, A. B., Godse, C., Vaidya, A., and R. A. Vaidya.  Plasmodium DNA fluoresces with berberine: A novel approach for diagnosis of malaria parasites.  Am. J. Clin. Pathol., 124: 408-412, 2005.
   
   
10. Furuya, T., Mu, J., Hayton, K., Liu, A., Duan, J., Nkrumah, L, Joy, D. A., Fidock, D. A. Fujioka, H., Vaidya, A. B., Wellems, T. E., and X.-Z Su.  Disruption of a Plasmodium falciparum gene linked to male sexual development causes early arrest in gametocytogenesis.  Proc. Natl. Acad. Sci. (USA), 102: 16813-16818, 2005.
    
    
11. Bosch, J., Turley, S., Daly, T. M., Bogh, S. M., Villasmil, M. L., Zhou, N., Morrisey, J. M., Vaidya, A. B., Bergman, L. W. and W. G. J. Hol.  Structure of the MTIP-MyoA complex, a key component of the malaria parasite invasion motor.  Proc. Natl. Acad. Sci. (USA), 103: 4852-4857, 2006.
    
    
12. Gogtay, N. J., Kshirsagar, N. A., and A. B. Vaidya.  Current challenges in drug-resistant malaria.  J. Postgrad. Med., 52: 241-242, 2006.
    
    
13. Mather, M. W., Henry, K. W., and A. B. Vaidya.  Mitochondrial drug targets in Apicomplexan parasites.  Current Drug Targets, 8: 49-60, 2007.
    
    
14. Painter, H. J., Morrisey, J. M., Mather, M. W., and A. B. Vaidya.  Specific role of mitochondrial electron transport in blood-stage Plasmodium falciparum.  Nature 446: 88-91, 2007.
    
    
15. Vaidya, A. B., Painter, H. J., Morrisey, J. M., and M. W. Mather.  The validity of mitochondrial dehydrogenases as antimalarial drug targets.  Trends Parasitol., 24: 8-9, 2008.