Limited Activity of Clofazimine as a Single Drug in a Mouse Model of Tuberculosis Exhibiting Caseous Necrotic Granulomas

New drugs and drugs with a novel mechanism of action are desperately needed to shorten the duration of tuberculosis treat-ment, to prevent the emergence of drug resistance, and to treat multiple-drug-resistant strains ofMycobacterium tuberculosis. Recently, there has been renewed interest in clofazimine (CFZ). In this study, we utilized the C3HeB/FeJ mouse model, possess-ing highly organized, hypoxic pulmonary granulomas with caseous necrosis, to evaluate CFZmonotherapy in comparison to results with BALB/c mice, which form only multifocal, coalescing cellular aggregates devoid of caseous necrosis. While CFZ treatment was highly effective in BALB/c mice, its activity was attenuated in the lungs of C3HeB/FeJ mice. This lack of efficacy was directly related to the pathological progression of disease in these mice, since administration of CFZ prior to the formation of hypoxic, necrotic granulomas reconstituted bactericidal activity in this mouse strain. These results support the continued use of mouse models of tuberculosis infection which exhibit a granulomatous response in the lungs that more closely resembles the pathology found in human disease. The StopTBPartnership, in conjunctionwith theWorldHealthOrganization, has set a goal of reducing tuberculosis (TB) in-cidence to less than one case per million by 2050 (1). If we hope to achieve this goal, we must more effectively employ the current resources in our anti-TB armament, as well as developing more efficacious drugs, diagnostics, and vaccines. Such a significant re