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.
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