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Antimicrobial Agents and Chemotherapy, May 2006, p. 1828-1834, Vol. 50, No. 5
0066-4804/06/$08.00+0     doi:10.1128/AAC.50.5.1828-1834.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Photoinactivation of Mycobacteria In Vitro and in a New Murine Model of Localized Mycobacterium bovis BCG-Induced Granulomatous Infection

Katie O'Riordan,¹ David S. Sharlin,^1, Jerome Gross,² Sung Chang,¹ Divya Errabelli,^1, Oleg E. Akilov,¹ Sachiko Kosaka,¹ Gerard J. Nau,^3, and Tayyaba Hasan^1*

Wellman Center for Photomedicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts,¹ Cutaneous Biology Research Center, Massachusetts General Hospital and Harvard Medical School, Charlestown Navy Yard, Charlestown, Massachusetts,² Division of Infectious Diseases, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts³

Received 19 December 2005/ Returned for modification 26 January 2006/ Accepted 22 February 2006

Treatment of tuberculosis is currently hindered by prolonged antibiotic regimens and the emergence of significant drug resistance. Alternatives and adjuncts to standard antimycobacterial agents are needed. We propose that a direct attack utilizing photosensitizers and light-based treatments may be effective in curtailing Mycobacterium tuberculosis in discrete anatomical sites in the most infectious phase of pulmonary tuberculosis. To demonstrate experimental proof of principle, we have applied established photodynamic therapy (PDT) technology to in vitro cultures and an in vivo mouse model using Mycobacterium bovis BCG. We report here in vitro and in vivo PDT efficacy studies and the use of a three-dimensional collagen gel as a delivery vehicle for BCG, subcutaneously inserted, to induce specifically localized granuloma-like lesions in mice. When a benzoporphyrin derivative was utilized as the photosensitive agent, exposure to light killed extracellular and intracellular BCG in significant numbers. Collagen scaffolds containing BCG inserted in situ in BALB/c mice for 3 months mimicked granulomatous lesions and demonstrated a marked cellular infiltration upon histological examination, with evidence of caseating necrosis and fibrous capsule formation. When 10⁵ BCG were present in the in vivo-induced granulomas, a significant reduction in viable mycobacterial cells was demonstrated in PDT-treated granulomas compared to those of controls. We conclude that PDT has potential in the treatment of localized mycobacterial infections, such as pulmonary granulomas and cavities.

Present address: Molecular and Cellular Biology Program, University of Massachusetts, Amherst, MA 01003.

Present address: Center for Human Genetics, Boston University, Boston, MA 02118.

Present address: Departments of Molecular Genetics and Biochemistry and Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pa.