title: Limited activity of clofazimine as a single drug in a mouse model of tuberculosis exhibiting caseous necrotic granulomas.
abstract: New drugs and drugs with a novel mechanism of action are desperately needed to shorten the duration of tuberculosis treatment, to prevent the emergence of drug resistance, and to treat multiple-drug-resistant strains of Mycobacterium tuberculosis. Recently, there has been renewed interest in clofazimine (CFZ). In this study, we utilized the C3HeB/FeJ mouse model, possessing highly organized, hypoxic pulmonary granulomas with caseous necrosis, to evaluate CFZ monotherapy 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.
authors.affiliation: Mycobacteria Research Laboratories, Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, Colorado, USA.
authors.forename: Scott M
authors.initials: SM
authors.lastname: Irwin
authors.affiliation: Mycobacteria Research Laboratories, Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, Colorado, USA.
authors.forename: Veronica
authors.initials: V
authors.lastname: Gruppo
authors.affiliation: Mycobacteria Research Laboratories, Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, Colorado, USA.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Brooks
authors.affiliation: Mycobacteria Research Laboratories, Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, Colorado, USA.
authors.forename: Janet
authors.initials: J
authors.lastname: Gilliland
authors.affiliation: Mycobacteria Research Laboratories, Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, Colorado, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Scherman
authors.affiliation: University of Colorado School of Medicine, Department of Microbiology, Aurora, Colorado, USA.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Reichlen
authors.affiliation: University of Colorado School of Medicine, Department of Microbiology, Aurora, Colorado, USA.
authors.forename: Rachel
authors.initials: R
authors.lastname: Leistikow
authors.affiliation: Boston University School of Medicine, Department of Pulmonary, Allergy, Sleep and Critical Care Medicine, Boston University, Boston, Massachusetts, USA.
authors.forename: Igor
authors.initials: I
authors.lastname: Kramnik
authors.affiliation: Center for Tuberculosis Research, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: Eric L
authors.initials: EL
authors.lastname: Nuermberger
authors.affiliation: University of Colorado School of Medicine, Department of Microbiology, Aurora, Colorado, USA.
authors.forename: Martin I
authors.initials: MI
authors.lastname: Voskuil
authors.affiliation: Mycobacteria Research Laboratories, Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, Colorado, USA anne.lenaerts@colostate.edu.
authors.forename: Anne J
authors.initials: AJ
authors.lastname: Lenaerts
mesh_terms: D000818:Animals; D000995:Antitubercular Agents / Q000627:therapeutic use*; D058491:Bacterial Load; D002991:Clofazimine / Q000627:therapeutic use*; D004195:Disease Models, Animal; D005260:Female; D006099:Granuloma / Q000188:drug therapy* / Q000473:pathology; D007371:Interferon-gamma / Q000235:genetics / Q000502:physiology; D008168:Lung / Q000382:microbiology; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D018345:Mice, Knockout; D008826:Microbial Sensitivity Tests; D009169:Mycobacterium tuberculosis / Q000187:drug effects; D009336:Necrosis; D014376:Tuberculosis / Q000150:complications / Q000188:drug therapy*
chemical_list: D000995:Antitubercular Agents; D007371:Interferon-gamma; D002991:Clofazimine