ANTIBIOTIC TRANSPORT IN MYCOBACTERIA INFECTED MACROPHAGE

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DESCRIPTION: (Adapted from Applicant's Abstract) Disease caused by Mycobacterium avium and Mycobacterium tuberculosis are major health care problems. These organisms cause intracellular infections, that is, they evade the normal host defenses by residing within the macrophages that would otherwise destroy them. Because of the specialized intracellular environment mycobacteria inhabit, antibiotics must achieve sufficient concentration in this compartment in order to be effective therapeutic agents. The major goal of this proposal to formulate new therapeutic strategies for these infections using modern tools of cell biology to target drugs to the mycobacteria-containing phagosomes. The focus is to characterize one of the cellular systems that influences both the total intracellular accumulation of many drugs and their distribution within the cell:organic anion transporters. One of the several different organic anion transporters mediates secretion of organic anions from the cell. This transporter may influence intracellular antibiotic disposition and may permit achieving adequate concentration of antibiotics in the treatment of intracellular infections. The proposed studies will (1) characterize organic anion transport in phagosomes containing mycobacteria; (2) measure the effect of mycobacteria infection of macrophages on the accumulation and subcellular localization of relevant antibiotics; (3) investigate the role of transmembrane pH gradients in these transport processes and (4) identify the plasma membrane proteins responsible for organic anion transport in these cells.