Disseminated infection with Mycobacterium-avium is the most common bacterial complication of AIDS in the United States. This project of the Drug Discovery Group on Opportunistic Infections utilizes a multidisciplinary approach to apply the sciences of animal modeling, biochemistry, cellular immunology, chemistry, medicinal chemistry, microbiology and molecular biology, and the computerized automated structure evaluation (CASE) program to develop more active drugs for the treatment of infections due to Mycobacterium-avium.
The Specific Aims of this proposal are: 1) To test the activity of a selected group of quinolone derivatives against a representative panel of M. avium strains using in vitro assays to determine the minimal inhibitory concentrations (MICs) and minimal bactericidal concentrations (MBCs) for extracellular organisms; and the concentrations inhibiting the intracellular growth of M. avium within human mononuclear phagocytes; 2) To determine whether the resistance of M. avium to quinolones reflects poor bacterial penetration of the drugs, or occurs at the level of DNA gyrase; and to assess the ability of the quinolones to breach the permeability barrier by comparing the MIC of each drug against M. avium with a) inhibition of the isolated mycobacterial DNA gyrase, and b) the MIC for recombinant M. smegmatis and E. coli expressing mycobacterial DNA gyrase; 3) To compare in vitro activity and in vivo efficacy of the most active quinolones using the immunodeficient mouse model of disseminated M. avium infection to be developed by Dr. Orme; 4) To analyze the data base provided by Specific Aims 1-3 so that determinants of quinolone activity against M. avium can be identified; to test the activity of available molecules containing these determinants, and to use the CASE program to predict molecules with optimal activity; 5) To synthesize optimally active quinolones and to test their activity in vitro and in vivo, alone and in combination with other drugs; and 6) To proceed with drug development of promising agents as appropriate.
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