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

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

National Institute of Chemistry Ljubljana
University of Ljubljana
John Innes Centre
University of Washington
Seattle Biomedical Research Institute

Research output: Contribution to journal › Letter › peer-review

2 Citations (Scopus)

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.

Original language	English
Pages (from-to)	2164-2170
Number of pages	7
Journal	ACS Medicinal Chemistry Letters
Volume	15
Issue number	12
DOIs	https://doi.org/10.1021/acsmedchemlett.4c00447
Publication status	Published - 12 Dec 2024
Externally published	Yes

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

bifurcated halogen bonds
crystal structure
DNA gyrase
M. tuberculosis
NBTIs

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10.1021/acsmedchemlett.4c00447Licence: CC BY

Cite this

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title = "Structural Aspects of Mycobacterium tuberculosis DNA Gyrase Targeted by Novel Bacterial Topoisomerase Inhibitors",

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.",

keywords = "bifurcated halogen bonds, crystal structure, DNA gyrase, M. tuberculosis, NBTIs",

author = "Maja Kokot and \{Hrast Rambaher\}, Martina and Lipeng Feng and Mitchenall, \{Lesley A.\} and Lawson, \{David M.\} and Anthony Maxwell and Tanya Parish and Nikola Minovski and Marko Anderluh",

year = "2024",

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day = "12",

doi = "10.1021/acsmedchemlett.4c00447",

language = "English",

volume = "15",

pages = "2164--2170",

journal = "ACS Medicinal Chemistry Letters",

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TY - JOUR

T1 - Structural Aspects of Mycobacterium tuberculosis DNA Gyrase Targeted by Novel Bacterial Topoisomerase Inhibitors

AU - Kokot, Maja

AU - Hrast Rambaher, Martina

AU - Feng, Lipeng

AU - Mitchenall, Lesley A.

AU - Lawson, David M.

AU - Maxwell, Anthony

AU - Parish, Tanya

AU - Minovski, Nikola

AU - Anderluh, Marko

PY - 2024/12/12

Y1 - 2024/12/12

N2 - 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.

AB - 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.

KW - bifurcated halogen bonds

KW - crystal structure

KW - DNA gyrase

KW - M. tuberculosis

KW - NBTIs

U2 - 10.1021/acsmedchemlett.4c00447

DO - 10.1021/acsmedchemlett.4c00447

M3 - Letter

AN - SCOPUS:85210127094

SN - 1948-5875

VL - 15

SP - 2164

EP - 2170

JO - ACS Medicinal Chemistry Letters

JF - ACS Medicinal Chemistry Letters

IS - 12

ER -

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

Abstract

UN SDGs

Keywords

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