TY - JOUR
T1 - Interaction of Quinolones Carrying New R1 Group with Mycobacterium leprae DNA Gyrase
AU - Park, Jong Hoon
AU - Yamaguchi, Tomoyuki
AU - Ouchi, Yuki
AU - Koide, Kentaro
AU - Pachanon, Ruttana
AU - Chizimu, Joseph Yamweka
AU - Mori, Shigetarou
AU - Kim, Hyun
AU - Mukai, Tetsu
AU - Nakajima, Chie
AU - Suzuki, Yasuhiko
N1 - Funding Information:
This work was supported in part by a grant from the Ministry of Education, Culture, Sports, Science and Technology (MEXT), Japan, and the Joint Research Program of the Research Center for Zoonosis Control, Hokkaido University to Yasuhiko Suzuki, and in part by Japan Agency for Medical Research and Development (AMED) under Grant Nos. JP19fm0108008, JP19fk0108042, JP19jm0510001, and JP18jk0210005 to Yasuhiko Suzuki. We are grateful to Wakunaga Pharmaceutical Co., Ltd. for providing WQ-3810, WQ-3334, WQ-4064, and WQ-4065.
Publisher Copyright:
© Copyright 2021, Mary Ann Liebert, Inc., publishers 2021.
PY - 2021/12
Y1 - 2021/12
N2 - 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.
AB - 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.
KW - DNA gyrase
KW - GyrB
KW - Mycobacterium leprae
KW - WQ-3334
KW - WQ-3810
UR - http://www.scopus.com/inward/record.url?scp=85121108246&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85121108246&partnerID=8YFLogxK
U2 - 10.1089/mdr.2020.0408
DO - 10.1089/mdr.2020.0408
M3 - Article
C2 - 34077282
AN - SCOPUS:85121108246
SN - 1076-6294
VL - 27
SP - 1616
EP - 1623
JO - Microbial Drug Resistance
JF - Microbial Drug Resistance
IS - 12
ER -
