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Interaction of Quinolones Carrying New R1 Group with Mycobacterium leprae DNA Gyrase

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Title: Interaction of Quinolones Carrying New R1 Group with Mycobacterium leprae DNA Gyrase
Authors: Park, Jong-Hoon Browse this author
Yamaguchi, Tomoyuki Browse this author
Ouchi, Yuki Browse this author
Koide, Kentaro Browse this author
Pachanon, Ruttana Browse this author
Chizimu, Joseph Yamweka Browse this author
Mori, Shigetarou Browse this author →KAKEN DB
Kim, Hyun Browse this author →KAKEN DB
Mukai, Tetsu Browse this author
Nakajima, Chie Browse this author →KAKEN DB
Suzuki, Yasuhiko Browse this author →KAKEN DB
Keywords: Mycobacterium leprae
DNA gyrase
Issue Date: 1-Dec-2021
Publisher: Mary Ann Liebert
Journal Title: Microbial drug resistance
Volume: 27
Issue: 12
Start Page: 1616
End Page: 1623
Publisher DOI: 10.1089/mdr.2020.0408
Abstract: Background: Leprosy is a chronic infectious disease caused by Mycobacterium leprae and the treatment of choice is ofloxacin (OFX). Specific amino acid substitutions in DNA gyrase of M. leprae have been reported leading to resistance against the drug. In our previous study, WQ-3810, a fluoroquinolone with a new R1 group (6-amino-3,5-difluoropyridin-2-yl) was shown to have a strong inhibitory activity on OFX-resistant DNA gyrases of M. leprae, and the structural characteristics of its R1 group was predicted to enhance the inhibitory activity. Methodology/Principal Finding: To further understand the contribution of the R1 group, WQ-3334 with the same R1 group as WQ-3810, WQ-4064, and WQ-4065, but with slightly modified R1 group, were assessed on their activities against recombinant DNA gyrase of M. leprae. An in silico study was conducted to understand the molecular interactions between DNA gyrase and WQ compounds. WQ-3334 and WQ-3810 were shown to have greater inhibitory activity against M. leprae DNA gyrase than others. Furthermore, analysis using quinolone-resistant M. leprae DNA gyrases showed that WQ-3334 had greater inhibitory activity than WQ-3810. The R8 group was shown to be a factor for the linkage of the R1 groups with GyrB by an in silico study. Conclusions/Significance: The inhibitory effect of WQ compounds that have a new R1 group against M. leprae DNA gyrase can be enhanced by improving the binding affinity with different R8 group molecules. The information obtained by this work could be applied to design new fluoroquinolones effective for quinolone-resistant M. leprae and other bacterial pathogens.
Rights: This is the accepted version of the following article: [Jong-Hoon Park, Tomoyuki Yamaguchi, Yuki Ouchi, Kentaro Koide, Ruttana Pachanon, Joseph Yamweka Chizimu, Shigetarou Mori, Hyun Kim, Tetsu Mukai, Chie Nakajima, and Yasuhiko Suzuki.Microbial Drug Resistance.Dec 2021.1616-1623.], which has now been formally published in final form at Microbial Drug Resistance at []. This original submission version of the article may be used for non-commercial purposes in accordance with the Mary Ann Liebert, Inc., publishers’ self-archiving terms and conditions.
Type: article (author version)
Appears in Collections:人獣共通感染症国際共同研究所 (International Institute for Zoonosis Control) > 雑誌発表論文等 (Peer-reviewed Journal Articles, etc)

Submitter: 鈴木 定彦

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