Here we integrated a number of data sets that utilized DNA microarrays covering spectrum of experimental conditions into a single analysis of dormant phase M. tuberculosis. Drug targets to specifically attack non-replicative bacilli emerging from our analysis were several regulatory elements that have the potential to force M. tuberculosis back into replicative mode. Other targets take advantage of the presumed hypoxic environment to state to disrupt redox balance, an altered respiratory chain, or the likely scarcity of ATP.
A recent paper was able to examine the transcriptional profile of M. tuberculosis from human lung samples [113]. The patients had active disease and were on chemotherapy so some of the granulomas were breaking up as part of reactivation. As a result a fraction of the cells were exposed to oxygen in vivo and possibly post excise as the resected samples were exposed to air. This could explain the up-regulation of a number of genes involved in aerobic metabolism. While a very important study we believe that these samples may be quite heterogeneous and might not entirely reflect the dormant phase.
The advent of large scale genomics covering not only the genomes of multiple bacterial species but also various strains within a pathogenic species, has lead to the application of comparative genomics analysis to derive lists of high priority gene targets. Genes can be ranked by a number of different criteria such as divergence from human genes; essentiality for both in vitro and infectious viability; homology across known pathogens; importance to pathogenic life cycle; tractability to small molecule inhibitors and so on. In reality, some seemingly obvious criteria have little pharmacological relevance. For example, the antibiotic rifampicin targets DNA-directed RNA polymerase which is highly conserved across all species including prokaryotes and humans yet it is a key member of the anti-TB compound quartet. While bioinformatics derived lists of prioritized genes can provide important starting points for new target discovery and to help organize genomic data [15], decisions on which TB drug development strategies to pursue requires additional context about pathogen biology, biochemistry, pharmacology and pathogenicity. Using this approach, we have suggested several potential drug development strategies against dormant phase M. tuberculosis which target key biosynthetic pathways.
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