TY - JOUR
T1 - WQ-3810 inhibits DNA gyrase activity in ofloxacin-resistant Mycobacterium leprae
AU - Park, Jong Hoon
AU - Yamaguchi, Tomoyuki
AU - Ouchi, Yuki
AU - Koide, Kentaro
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, Japan, and the Joint Research Program of the Research Center for Zoonosis Control, Hokkaido University to YS, and in part by Japan Agency for Medical Research and Development under Grant Number JP19fm0108008, JP19fk0108042, JP19jm0510001, and JP18jk0210005 to YS. We are grateful to Wakunaga Pharmaceutical Co. Ltd. for providing WQ-3810.
Funding Information:
This work was supported in part by a grant from the Ministry of Education, Culture, Sports, Science and Technology, Japan , and the Joint Research Program of the Research Center for Zoonosis Control, Hokkaido University to YS, and in part by Japan Agency for Medical Research and Development under Grant Number JP19fm0108008 , JP19fk0108042 , JP19jm0510001 , and JP18jk0210005 to YS. We are grateful to Wakunaga Pharmaceutical Co., Ltd. for providing WQ-3810.
Publisher Copyright:
© 2019 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases
PY - 2020/4
Y1 - 2020/4
N2 - Background: Mycobacterium leprae causes leprosy and ofloxacin is used to control this bacterium. However, specific amino acid substitutions in DNA gyrases of M. leprae interferes with the effect of ofloxacin. Methodology/principal findings: Here we tested the inhibitory effect of WQ-3810 on DNA gyrases in M. leprae, using recombinant gyrases. We theorized that WQ-3810 and DNA gyrases interacted, which was tested in silico. Compared with control drugs like ofloxacin, WQ-3810 showed a better inhibitory effect on ofloxacin-resistant DNA gyrases. The in-silico study showed that, unlike control drugs, a specific linkage between a R1 group in WQ-3810 and aspartic acid at position 464 in the subunit B of DNA gyrases existed, which would enhance the inhibitory effect of WQ-3810. This linkage was confirmed in a further experiment, using recombinant DNA gyrases with amino acid substitutions in subunits B instead. Conclusions/significance: The inhibitory effect of WQ-3810 was likely enhanced by the specific linkage between a R1 group residue in its structure and DNA gyrases. Using interactions like the one found in the present work may help design new fluoroquinolones that contribute to halt the emergence of antibiotic-resistant pathogens.
AB - Background: Mycobacterium leprae causes leprosy and ofloxacin is used to control this bacterium. However, specific amino acid substitutions in DNA gyrases of M. leprae interferes with the effect of ofloxacin. Methodology/principal findings: Here we tested the inhibitory effect of WQ-3810 on DNA gyrases in M. leprae, using recombinant gyrases. We theorized that WQ-3810 and DNA gyrases interacted, which was tested in silico. Compared with control drugs like ofloxacin, WQ-3810 showed a better inhibitory effect on ofloxacin-resistant DNA gyrases. The in-silico study showed that, unlike control drugs, a specific linkage between a R1 group in WQ-3810 and aspartic acid at position 464 in the subunit B of DNA gyrases existed, which would enhance the inhibitory effect of WQ-3810. This linkage was confirmed in a further experiment, using recombinant DNA gyrases with amino acid substitutions in subunits B instead. Conclusions/significance: The inhibitory effect of WQ-3810 was likely enhanced by the specific linkage between a R1 group residue in its structure and DNA gyrases. Using interactions like the one found in the present work may help design new fluoroquinolones that contribute to halt the emergence of antibiotic-resistant pathogens.
KW - DNA gyrase
KW - Mycobacterium leprae
KW - Recombinant molecules
KW - WQ-3810
UR - http://www.scopus.com/inward/record.url?scp=85076462989&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85076462989&partnerID=8YFLogxK
U2 - 10.1016/j.jiac.2019.10.013
DO - 10.1016/j.jiac.2019.10.013
M3 - Article
C2 - 31839561
AN - SCOPUS:85076462989
SN - 1341-321X
VL - 26
SP - 335
EP - 342
JO - Journal of Infection and Chemotherapy
JF - Journal of Infection and Chemotherapy
IS - 4
ER -
