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Science: Compound Kills TB Pathogen in Cell Cultures and Mice
Lungs of a 21-year-old South African patient dying from MDR-TB.
[Image courtesy of John McKinney]
A compound that blocks the tuberculosis pathogen from building its cell walls shows promise for a new drug to fight the tuberculosis pandemic, an international research team reports in the 20 March issue of Science.
Tuberculosis is a major public health problem, linked tightly to poverty and HIV/AIDS, and drug-resistant strains continue to emerge, making the need for new drugs more acute than ever. The new research is being published just before World TB day, March 24th, which is designed to build public awareness that tuberculosis remains an epidemic in much of the world, causing the deaths of several million people each year, mostly in the developing world, according to the Stop TB Partnership.
The research team, which was led by Stewart Cole of the Global Health Institute at the École Polytechnique Fédérale de Lausanne and included researchers from around the world, has identified a compound that kills infected cell cultures and bacteria in mice. Sulfur is unusually common in anti-tubercular drugs, so the researchers began by synthesizing a series of sulfur-containing compounds called heterocycles and testing their activity against bacteria and fungi.
Killing effect of BTZ043 on individual cells. M. tuberculosis growing in a microfluidics device was monitored at 2 h intervals by fluorescence microscopy. Representative frames are shown at 96 h intervals with (+) or without (-) drug. BTZ043 was added at 96 h (200 ng/ml) and maintained in the culture until 336 h when drug-free medium was introduced for the remainder of the experiment. Note the disappearance of GFP-labeled bacilli due to lysis within the first 96 h, the absence of regrowth and the extensive cellular damage as evidenced by propidium iodide uptake at the experiment's end (604 h). At this time all cells, including those positive for GFP, stained with propidium iodide. The white scale bar represents 5 µm.
[Image courtesy of Science/AAAS]
They narrowed their search down to a class called nitro-benzothiazinones (or "BTZ") that were potent against mycobacteria and then pinpointed one member of this class, called BTZ043, that was particularly promising. In test-tube experiments, the compound killed Mycobacterium tuberculosis when used in concentrations comparable to those of frontline TB drug treatments. And it was almost as effective as one of these drugs in reducing the bacterial levels in the lungs and spleens of infected mice, with no side-effects evident after one month.
The compound appears to target a component of Mycobacterium's cell-wall-building machinery that has never before been "drugged" in any micro-organism, according to the researchers.
19 March 2009
Time-lapse microscopy of BTZ-sensitive M. tuberculosis strain (H37Rv) exposed to BTZ043. Bacteria were cultivated at 37° C in a continuous-flow microfluidic device and visualized using the 100X oil immersion objective. Images were acquired at 2 h intervals. Cells were fed standard 7H9 medium for 98 h and then exposed to BTZ043 at 0.2 µg/ml for 240 h. The compound was then washed out and the remaining cells were fed standard 7H9 medium for another 265 h. This treatment resulted in lysis of the majority of bacteria. The minority of cells that remained GFP- positive (a) and phase dense (b) after BTZ exposure did not resume growth after BTZ washout. At the end of the experiment the remaining bacteria were stained with propidium iodide (PI), which selectively stains cells with compromised cell wall integrity. The majority of the GFP-positive bacteria were also PI-positive, suggesting that the cell wall permeability barrier had been ruptured and these cells were most likely dead.
[Video file courtesy of Science/AAAS]