Inhibitors of PknB as Potential Anti-Tuberculosis Agents
Author Information
Author(s): Kathryn E.A. Lougheed, Simon A. Osborne, Barbara Saxty, David Whalley, Tim Chapman, Nathalie Bouloc, Jasveen Chugh, Timothy J. Nott, Dony Patel, Vicky L. Spivey, Catherine A. Kettleborough, Justin S. Bryans, Debra L. Taylor, Stephen J. Smerdon, Roger S. Buxton
Primary Institution: MRC National Institute for Medical Research
Hypothesis
Can small molecule inhibitors of the essential kinase PknB effectively inhibit the growth of Mycobacterium tuberculosis?
Conclusion
The study identified several inhibitors of PknB, but their effectiveness against M. tuberculosis was limited due to poor cell wall permeability.
Supporting Evidence
- PknB is essential for the growth of Mycobacterium tuberculosis.
- Over 50,000 compounds were screened to find effective inhibitors.
- Lead compounds showed potency in the nanomolar range in vitro.
- Compounds were less effective in vivo, indicating potential issues with cell wall permeability.
- Cross-reactivity with other kinases was observed.
- Efforts to improve drug delivery through cell wall modifications were unsuccessful.
Takeaway
Researchers looked for drugs that could stop a germ called tuberculosis from growing by blocking a specific protein, but the drugs didn't work as well inside the body as they did in tests.
Methodology
The study involved screening over 50,000 compounds for their ability to inhibit PknB activity and testing the most promising candidates in vitro and in macrophage models.
Limitations
The inhibitors showed poor activity against whole cells compared to in vitro results, and the study could not determine if cell wall permeability was the main issue.
Digital Object Identifier (DOI)
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