Pneumocystis carinii is a pulmonary opportunistic pathogen and a causative agent of pneumonia in immunocompromised individuals. It causes the most common opportunistic infection, and is a major cause of death, in AIDS patients. Since there is a high incidence of adverse reactions among AIDS patients to existing anti-P. carinii treatments, the worldwide economic and medical burdens caused by P. carinii are severe. The existence of P. carinii refractive or resistant to current antibiotics highlights the necessity of developing innovative technologies to control this pathogen. Novel antibiotics capable of arresting the growth of microbial pathogens are being developed. These drugs will selectively inhibit the function of aminoacyl-tRNA synthetases, essential enzymes involved in protein synthesis. Since the aminoacyl-tRNA synthetases have diverged between species, it is possible to rationally design drugs that inhibit these enzymes from similar pathogens, but which are not toxic to humans. It is proposed that genes from P. carinii encoding aminoacyl-tRNA synthetases will be characterized, and candidate drugs will be assayed to determine if they have anti-microbial activities related to their interfering with the activity of the encoded synthetases. Tester strains of Escherichia coli and yeast, which are deleted for their endogenous synthetase, will be developed for an in vivo assay to analyze the effect drugs have on the cloned P. carinii and human synthetases.
