Novel drug targets for tuberculosis therapy

NextGenRnD® Solution No. 4

The attenuated strain of Mycobacterium bovis, known as Bacillus Calmette-Guérin (BCG), is the most successful vaccine against human severe childhood tuberculosis. The genome of Mycobacterium bovis is more than 99.9% identical to the genome of the Mycobacterium tuberculosis. The BCG vaccination is highly cost-effective and is recommended as a supplemental strategy for the chemotherapy of active tuberculosis in humans1. Approximately 100 million doses of BCG vaccine are distributed worldwide each year.

There are three genomic regions of difference (RD1–3) that were deleted from the genome of BCG vaccine. The precise junctions and the breakpoints in the Mycobacterium bovis genome, at which the RD1, RD2, and RD3 deletions occurred were identified2. The absence of these regions of difference from the Mycobacterium bovis genome defines the transition from virulent strains causing tuberculosis to the attenuated BCG strains used to prevent the disease. It was found that all clinical isolates of Mycobacterium bovis as well as virulent laboratory strains (e.g., H37Rv) contained the genomic RD1 and RD2, whereas RD3 was not 100% conserved in clinical isolates. Importantly, all BCG sub-strains had the RD1 and RD3 deleted from their genomes and some of BCG sub-strains contained the RD2 deletion. It was proposed that RD1 regulates multiple genetic loci and that the loss of BCG virulence can be explained by some regulatory mutation2.


We analyzed Mycobacterium bovis and species of another genus of bacteria with a smaller genome infecting beef and cattle. Bacteria infecting the same host might have common genes essential for pathogenesis. Reduction of bacterial genome size implies that only the genes absolutely essential for the pathogenesis in beef and cattle must be retained.

In this Solution, NextGenRnD reports the identification of two genes that might be responsible for the Mycobacterium bovis virulence attenuation. Our findings suggest another explanation for the attenuation of BCG virulence.

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