Research Highlights: CRISPR-based genetics and Tuberculosis Drug Discovery


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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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