WQ-3810 inhibits DNA gyrase activity in ofloxacin-resistant Mycobacterium leprae.
DNA gyrase
Mycobacterium leprae
Recombinant molecules
WQ-3810
Journal
Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy
ISSN: 1437-7780
Titre abrégé: J Infect Chemother
Pays: Netherlands
ID NLM: 9608375
Informations de publication
Date de publication:
Apr 2020
Apr 2020
Historique:
received:
12
09
2019
revised:
08
10
2019
accepted:
15
10
2019
pubmed:
17
12
2019
medline:
15
12
2020
entrez:
17
12
2019
Statut:
ppublish
Résumé
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. 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. 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.
Sections du résumé
BACKGROUND
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
RESULTS
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
CONCLUSIONS
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.
Identifiants
pubmed: 31839561
pii: S1341-321X(19)30330-7
doi: 10.1016/j.jiac.2019.10.013
pii:
doi:
Substances chimiques
Anti-Bacterial Agents
0
Azetidines
0
Fluoroquinolones
0
WQ-3810
0
Ofloxacin
A4P49JAZ9H
DNA Gyrase
EC 5.99.1.3
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
335-342Informations de copyright
Copyright © 2019 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of Competing Interest There is no conflict of interest.