Structural Aspects of <i>Mycobacterium tuberculosis</i> DNA Gyrase Targeted by Novel Bacterial Topoisomerase Inhibitors
In this Letter, we present a small series of novel bacterial topoisomerase inhibitors (NTBIs) that exhibit both potent inhibition of <i>Mycobacterium tuberculosis</i> DNA gyrase and potent antimycobacterial activity. The disclosed crystal structure of <i>M. tuberculosis</i> DNA gyrase in complex with DNA and compound <b>5</b> from this NBTI series reveals the binding mode of an NBTI in the GyrA binding pocket and confirms the presence and importance of halogen bonding for the excellent on-target potency. In addition, we have shown that compound <b>5</b> is a promising <i>M. tuberculosis</i> DNA gyrase inhibitor, with an IC<sub>50</sub> for <i>M. tuberculosis</i> gyrase of 0.096 μM, and it has potent activity against <i>M. tuberculosis</i>, with an IC<sub>50</sub> of 0.165 μM.
Authors
- Marko Anderluh (ORCID: https://orcid.org/0000-0003-1768-8246)
- Martina Hrast (ORCID: https://orcid.org/0000-0003-0488-2445)
- Tanya Parish (ORCID: https://orcid.org/0000-0001-7507-0423)
- Nikola Minovski (ORCID: https://orcid.org/0000-0003-0039-2246)
- Lipeng Feng (ORCID: https://orcid.org/0000-0003-1696-6435)
- David M. Lawson (ORCID: https://orcid.org/0000-0002-7637-4303)
- Anthony Maxwell (ORCID: https://orcid.org/0000-0002-5756-6430)
- Lesley A. Mitchenall (ORCID: https://orcid.org/0000-0002-0063-1991)
- Maja Kokot (ORCID: https://orcid.org/0000-0002-9307-330X)
Institutions
- John Innes Centre (GB)
- Infectious Disease Research Institute (US)
- University of Ljubljana (SI)
- University of Washington (US)
- Norwich Research Park (GB)
- National Institute of Chemistry (SI)
Publication Details
- Journal
- ACS Medicinal Chemistry Letters
- Published
- 2024-11-22
- DOI
- https://doi.org/10.1021/acsmedchemlett.4c00447
- Citations
- 4
- Primary Topic
- Cancer therapeutics and mechanisms
- Type
- article
- Field-Weighted Citation Impact
- 0.94
Funders
- Fred Hutchinson Cancer Research Center
- University of Washington
- Seattle Children's Research Institute
- Children’s Hospital of Wisconsin Research Institute
- Diamond Light Source
- Javna Agencija za Raziskovalno Dejavnost RS
- Center for AIDS Research, University of Washington
- Biotechnology and Biological Sciences Research Council
- National Institute of Allergy and Infectious Diseases