Recently in the United States there have been simultaneous increases in the incidence of tuberculosis and the proportion of cases caused by drug- resistant strains. These trends, together with near-stagnation in the development of new agents with anti-tuberculous activity, pose a formidable challenge to efforts to contain the spread of this important and virulent human pathogen. The cell wall of Mycobacterium tuberculosis includes a thick peptidoglycan layer. Many, and possibly most strains of M. tuberculosis make a cell-associated beta-lactamase. The demonstration that M. tuberculosis is relatively susceptible in vitro to benzylpenicillin-cloxacillin and ampicillin-clavulanic acid, and that this susceptibility derives from beta-lactamase inhibition, suggest the potential utility of some beta-lactams and beta-lactam-beta-lactamase inhibitor combinations in the chemoprophylaxis and therapy of infection by drug-resistant strains. Furthermore, some antibiotics traditionally believed to be restricted to extracellular body fluids, including the aminoglycosides and beta-lactams, can be concentrated within macrophages when delivered via liposomes. The improved targeting of intracellular bacteria made possible by such techniques encourages a re-evaluation of the role of beta-lactams and beta-lactam-beta-lactamase combinations in the management of tuberculosis. The goal of this project is to clarify the interactions between M. tuberculosis, its beta-lactamase, various beta-lactams and beta-lactam-beta-lactamase inhibitor combinations, macrophages and liposomal delivery systems with the longterm goal of developing alternative chemoprophylactic and therapeutic regimens. The investigation will include the molecular and kinetic characterization of purified M. tuberculosis beta-lactamase with the identification of hydrolysis-resistant beta-lactams and beta-lactam-beta-lactamase combinations. Stable agents will be tested for inhibitory and bactericidal activity in vitro, and potent agents will be tested further for activity against intracellular tubercle bacilli within cultured human macrophages. Antibiotic-containing liposomes will be used to improve the intracellular delivery of drug. An improved understanding of the interaction between the beta-lactamase of M. tuberculosis and beta- lactams at the molecular level has the potential to identify, or lead to the development of, additional agents for the management of multidrug- resistant tuberculosis.
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