CRISPR-based genetics and Tuberculosis Drug Discovery
- Tuberculosis (TB) is caused by a bacterium called Mycobacterium tuberculosis (Mtb).
- The bacteria usually attack the lungs, but TB bacteria can attack any part of the body such as the kidney, spine, and brain.
- Professor Stewart Cole is an internationally acclaimed scientist, and has published more than 350 scientific papers on infectious diseases, most notably tuberculosis and leprosy.
- Professor Cole and colleagues determined the complete genome sequence of Mtb.
- This was a landmark achievement that signals a new age in TB drug discovery.
- With the genome sequence in hand, drug discoverers suddenly had thousands of new potential targets to explore.
- But the excitement has since faded.
- It is unquestioned that genomics has transformed our understanding of the biology of this pathogen.
- However, the expectation that the Mtb genome sequence would rapidly lead to new therapeutic interventions remains unfulfilled.
- One of the many reasons for this unrealized potential is that our tools to systematically question the Mtb genome and its drug targets have been limited.
- This study argue that the recent development of robust CRISPR-based genetics in Mtb overcomes many prior limitations and holds the potential to close the gap between genomics and TB drug discovery.
- Prof. Cole discuss how this tool might improve TB antibiotic discovery.
- How can we bias target-based drug discovery towards targets with higher chances of success?
- Most clinically relevant antibiotics target a very limited set of biological pathways.
- The evolution of drug resistance to existing antibiotics is making the targeting of these pathways increasingly ineffective.
- Thus, it is clear that TB antibiotic discovery needs to expand target space.
- For the hundreds of compounds that have anti-tubercular activity but don’t understand how they work, how can we discover their mechanisms of action?
- The lack of understanding of compound mechanisms of action is a major impediment to the preclinical development of potentially hundreds of promising new compounds to treat TB.
- Treating active TB with monotherapy does not work.
- All evidence suggests that, at least for the foreseeable future, TB will be treated with combination chemotherapy.
- Thus, a critical question facing TB antibiotic discoverers is “how do we rationally develop new drug combinations that are significantly more potent than what we have now?”
- The past 20 years have seen slow progress in the TB drug pipeline.
- While optimism is warranted, significant challenges remain.
- The application of these new functional genomic tools may yield a more robust TB antibiotic discovery platform, thereby helping to realize the 20-year-old aspiration of the sequencing of the Mtb genome to develop new drugs to control this disease.
Sources:
Rock J (2019) Tuberculosis drug discovery in the CRISPR era. PLoS Pathog 15(9): e1007975. https://doi.org/10.1371/journal.ppat.1007975
https://actu.epfl.ch/news/stewart-cole-appointed-president-of-institut-pas-3/
https://www.cdc.gov/tb/topic/basics/default.htm
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