Structural Aspects of Mycobacterium tuberculosis DNA Gyrase Targeted by Novel Bacterial Topoisomerase Inhibitors

Maja Kokot; Martina Hrast Rambaher; Lipeng Feng; Lesley A Mitchenall; David M Lawson; Anthony Maxwell; Tanya Parish; Nikola Minovski; Marko Anderluh

doi:10.1021/acsmedchemlett.4c00447

Structural Aspects of Mycobacterium tuberculosis DNA Gyrase Targeted by Novel Bacterial Topoisomerase Inhibitors

ACS Med Chem Lett. 2024 Nov 22;15(12):2164-2170. doi: 10.1021/acsmedchemlett.4c00447. eCollection 2024 Dec 12.

Authors

Maja Kokot^{1

2}, Martina Hrast Rambaher², Lipeng Feng^{3

4}, Lesley A Mitchenall^{3

4}, David M Lawson^{3

5}, Anthony Maxwell^{3

4}, Tanya Parish^{6

7}, Nikola Minovski¹, Marko Anderluh²

Affiliations

¹ Theory Department, Laboratory for Cheminformatics, National Institute of Chemistry, Hajdrihova 19, 1001 Ljubljana, Slovenia.
² Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Ljubljana, Aškerčeva cesta 7, 1000 Ljubljana, Slovenia.
³ Department of Biological Chemistry, John Innes Centre, Norwich Research Park, Norwich NR4 7UH, U.K.
⁴ Department of Molecular Microbiology, John Innes Centre, Norwich Research Park, Norwich NR4 7UH, U.K.
⁵ Department of Biochemistry & Metabolism, John Innes Centre, Norwich Research Park, Norwich NR4 7UH, U.K.
⁶ School of Medicine, University of Washington, Seattle, Washington 98195, United States.
⁷ Center for Global Infectious Disease Research, Seattle Children's Research Institute, Seattle, Washington 98105, United States.

Abstract

In this Letter, we present a small series of novel bacterial topoisomerase inhibitors (NTBIs) that exhibit both potent inhibition of Mycobacterium tuberculosis DNA gyrase and potent antimycobacterial activity. The disclosed crystal structure of M. tuberculosis DNA gyrase in complex with DNA and compound 5 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 5 is a promising M. tuberculosis DNA gyrase inhibitor, with an IC₅₀ for M. tuberculosis gyrase of 0.096 μM, and it has potent activity against M. tuberculosis, with an IC₅₀ of 0.165 μM.