Abstract

Pneumocystis carinii (PcP) remains an important cause of infection in immunocompromised hosts including patients with AIDS. The most widely utilized therapy is trimethoprim-sulfamethoxazole (TMP-SMX). Recent concerns have arisen over development of mutations to the DHPS locus, which mediates sensitivity to SMX. Accordingly, Dr. Cushion proposes new strategies to develop treatments for Pneumocystis based upon a better understanding of the sterol and mitochondrial metabolism pathways as potential targets for therapy. They propose to first identify efficacious compounds which target enzymatic steps in the sterol biosynthetic and mitochondrial pathways of Pc using in vitro viability assay. Under the second aim, they will assess the potential mechanisms of action of these inhibitors on each pathway by analysis of gene expression using macroarrays. In the third aim, they will attempt to identify synergistic combinations of the sterol ad mitochondrial inhibitors within and between these pathways by construction of inhibitor isobolograms. Finally, they will select the most efficacious combinations of agents and evaluate their effects on gene expression again using the macroarray approach.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI050450-04
Application #
6896098
Study Section
Special Emphasis Panel (ZRG1-AARR-1 (04))
Program Officer
Lambros, Chris
Project Start
2002-06-01
Project End
2007-05-31
Budget Start
2005-06-01
Budget End
2006-05-31
Support Year
4
Fiscal Year
2005
Total Cost
$344,250
Indirect Cost

  Institution

Name
University of Cincinnati
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
041064767
City
Cincinnati
State
OH
Country
United States
Zip Code
45221

  Publications

Sesterhenn, Thomas M; Slaven, Bradley E; Keely, Scott P et al. (2010) Sequence and structure of the linear mitochondrial genome of Pneumocystis carinii. Mol Genet Genomics 283:63-72
Cushion, Melanie T; Collins, Margaret S; Linke, Michael J (2009) Biofilm formation by Pneumocystis spp. Eukaryot Cell 8:197-206
Cushion, Melanie T; Walzer, Peter D (2009) Preclinical drug discovery for new anti-pneumocystis compounds. Curr Med Chem 16:2514-30
Beck, James M; Cushion, Melanie T (2009) Pneumocystis workshop: 10th anniversary summary. Eukaryot Cell 8:446-60
Sesterhenn, Thomas M; Cushion, Melanie T; Slaven, Bradley E et al. (2006) Sequence of the mitochondrial genome of Pneumocystis carinii: implications for biological function and identification of potential drug targets. J Eukaryot Microbiol 53 Suppl 1:S154-5
Joffrion, Tiffany M; Collins, Margaret S; Cushion, Melanie T (2006) Microaerophilic conditions increase viability and affect responses of Pneumocystis carinii to drugs in vitro. J Eukaryot Microbiol 53 Suppl 1:S117-8
Vanden Eynde, Jean Jacques; Mayence, Annie; Huang, Tien L et al. (2004) Novel bisbenzamidines as potential drug candidates for the treatment of Pneumocystis carinii pneumonia. Bioorg Med Chem Lett 14:4545-8