Acquired Immune Deficiency Syndrome (AIDS) patients succumb to many opportunistic infections (OI), chief among them being those caused by Mycobacterium avium-complex (MAC). Unlike the other OI's involved in AIDS, MAC can cause serious disease even in immunologically normal people, however, the disease is progressive, disseminated and very difficult to treat in AIDS patients. At present, therapeutic approaches to treat this OI are very limited since available drugs are minimally effective. Studies envisaged in this grant application are planned with a multifaceted approach of drug discovery, instead of relying on one or two methods of evaluation. In order to allow a thorough characterization of therapeutic potential, these studies will be confined to six promising groups of compounds (clofazamine analogues, aminoglycosides, ethambutol analogues, floroquinolones, vitamin K derivatives, and gangamicin analogues), instead of attempting to screen widely unrelated drugs. Initial screening of a large number of drugs and antibiotics will consist of thoroughly standardized in vitro radiometric methods. Agents discovered in this initial screening will be followed by a series of simulated in vivo studies using constant, dynamic or pulsed exposure of the organisms to the active agents, to categorize further their potential antibacterial activity. Further evaluation of their definitive chemotherapeutic potential will be accomplished using the beige mouse model under varied treatment protocols. To further establish the clinical value of the prospective agent, we will evaluate the intracellular killing of persisting mycobacteria using cultured murine and human macrophage cell lines. A very important component of this grant application is to coordinate and compliment the clinical studies under the AIDS Clinical Trials Unit (ACTU) in Chicago, by conducting parallel laboratory studies with drugs currently being used and those discovered under this grant, against the patient's own organism. We will monitor clinical response by laboratory studies using the patients MAC isolates and their sera obtained during chemotherapy. It is hoped these studies will enable discovery and development of some powerful drugs for MAC disease in AIDS and to offer laboratory support to monitor clinical response.
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