BBB Seminar: Gareth Griffiths
Development of biodegradable nanoparticles enclosing antibiotics against Mycobacterium tuberculosis in macrophages and in a zebrafish model system
Department of Molecular Biosciences, University of Oslo
The only currently available treatment against tuberculosis is the standard 6-8 month oral treatment with up to four antibiotics, rifampicin, isoniazid, ethambutol and pyrazinamide. The need for such long treatment is hampered by patient non-compliance, leading to multi-drug resistance. One drawback of this standard protocol is that the antibiotics are rapidly degraded or excreted and must therefore be administered daily. An elegant alternative approach being pursued in a number of groups in different animal models is to encapsulate the antibiotics in biodegradable nanoparticles (NPs). When administered either orally or via the lung-aerosol route these NPs appear to be able to cross epithelial barriers and to be taken up via phagocytosis by macrophages, the cells wherein pathogenic mycobacteria such as M. tuberculosis (M.tb) primarily reside. This field has been pioneered in particular by our collaborator Gopal Khuller in India, but also by other groups (see Griffiths et al, 2010. Nat. Rev. Microbiol. 8, 827). Striking results using a guinea pig model of M.tb by Khuller’s group have shown that M.tb infection of these animals can be cleared either by 45 daily doses of free antibiotics or by only 3-5 doses of antibiotics administered in poly lactide, co-glycolide (PLGA) NPs (Pandey et al, 2003. J. Antimicrob. Chemother. 52, 981). Despite these, and other striking results in this field, very little is known about the pathways taken by the NPs after the different routes of administration. To provide more insight into the mechanisms and routes taken in vivo by the NPs we have recently set up two systems to address the efficacy by which rifampicin-enclosing PLGA NPs can kill mycobacteria. 1. Primary mouse bone marrow macrophages infected with red fluorescent BCG bacteria, and 2. A zebrafish model of tuberculosis using red and green variants of M. marinum, a system pioneered by the group of Ramakrishnan (see Lesley and Ramakrishnan, 2008. Curr. Opin. Microbiol. 11, 277). In this presentation I will summarize the current standing of our group’s progress on these two systems.
Host: Hans-Hermann Gerdes, Department of Biomedicine