The applicant states that although thousands of sulfa drugs have been synthesized and dozens have been used clinically, very few have been tested against P. carinii. Similarly, p-aminosalicylic acid (PAS) and its derivatives, which are antitubercular DHPS inhibitors, have never been tested against P. carinii.
The aim of this proposal is to identify members of these two classes of drugs which might be useful in the treatment of PCP. The inhibitory effects of sulfones, sulfonamides, and PAS derivatives on P. carinii folate biosynthesis in culture will be measured. By following the conversion of [3H]pABA into folates (using milk folate binding protein) drug effects can be measured on P. carinii which are multiplying in the presence of feeder layer cells in a manner which is easier and more quantitative than counting trophozoite. In order to better understand the biochemical effects of these drugs, they will also be evaluated as inhibitors of the DHPS activity of crude parasite homogenates and of purified enzyme. The applicant will also determine whether these drugs affect [3H]pABA uptake and or de novo pABA biosynthesis, and compare their abilities to be taken up by parasites by measuring competition with [14C]-sulfamethoxasole uptake. The most effective compounds will undergo evaluation for activity in vivo in P. carinii-infected rats and be used as lead compounds for the selection and/or synthesis of related agents.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
1R01AI031775-01A2
Application #
3146749
Study Section
AIDS and Related Research Study Section 4 (ARRD)
Project Start
1993-01-01
Project End
1995-12-31
Budget Start
1993-01-01
Budget End
1993-12-31
Support Year
1
Fiscal Year
1993
Total Cost
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Type
Schools of Public Health
DUNS #
791277940
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
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Kazanjian, P; Armstrong, W; Hossler, P A et al. (2001) Pneumocystis carinii cytochrome b mutations are associated with atovaquone exposure in patients with AIDS. J Infect Dis 183:819-22
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Kazanjian, P; Locke, A B; Hossler, P A et al. (1998) Pneumocystis carinii mutations associated with sulfa and sulfone prophylaxis failures in AIDS patients. AIDS 12:873-8
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Hong, Y L; Hossler, P; Bartlett, M et al. (1996) Evaluation of sulfa drugs against recombinant Pneumocystis carinii dihydropteroate synthetase and in vivo. J Eukaryot Microbiol 43:40S
Lane, B; Hossler, P; Bartlett, M et al. (1996) Sulfa resistance in mouse-derived Pneumocystis carinii. J Eukaryot Microbiol 43:39S
Ittarat, I; Asawamahasakda, W; Bartlett, M S et al. (1995) Effects of atovaquone and other inhibitors on Pneumocystis carinii dihydroorotate dehydrogenase. Antimicrob Agents Chemother 39:325-8
Hong, Y L; Bartlett, M S; Queener, S et al. (1995) Pteroylpolyglutamate synthesis by lung- and culture-derived Pneumocystis carinii. FEMS Microbiol Lett 134:251-4

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