TY - JOUR
T1 - WQ-3810
T2 - A new fluoroquinolone with a high potential against fluoroquinolone-resistant Mycobacterium tuberculosis
AU - Ouchi, Yuki
AU - Mukai, Tetsu
AU - Koide, Kentaro
AU - Yamaguchi, Tomoyuki
AU - Park, Jong Hoon
AU - Kim, Hyun
AU - Yokoyama, Kazumasa
AU - Tamaru, Aki
AU - Gordon, Stephen V.
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 , for 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 (AMED) under Grant Number JP19fm0108008 , JP19fk0108042 , JP19jm0510001 , and JP18jk0210005 to YS.
Publisher Copyright:
© 2019 Elsevier Ltd
PY - 2020/1
Y1 - 2020/1
N2 - Fluoroquinolone (FQ) resistance in Mycobacterium tuberculosis (Mtb), caused by amino acid substitutions in DNA gyrase, has been increasingly reported worldwide. WQ-3810 is a newly developed FQ that is highly active against FQ-resistant pathogens; however, its activity against Mtb has not been evaluated. Herein we examined the efficacy of WQ-3810 against Mtb through the use of recombinant Mtb DNA gyrases. In addition, in vitro antimycobacterial activity of WQ-3810 was evaluated against recombinant Mtb var. bovis Bacille Calmette–Guérin strains in which gyrase-coding genes were replaced with Mtb variants containing resistance-conferring mutations. WQ-3810 showed a higher inhibitory activity than levofloxacin against most recombinant DNA gyrases with FQ-resistance mutations. Furthermore, WQ-3810 showed inhibition even against a DNA gyrase variant harboring a G88C mutation which is thought to confer the highest resistance against FQs in clinical Mtb isolates. In contrast, the FQ susceptibility test showed that WQ-3810 had relatively weak mycobactericidal activity compared with moxifloxacin. However, the combination of WQ-3810 and ethambutol showed the greatest degree of synergistic activity against recombinant strains. Since FQs and ethambutol have been used in multi-drug therapy for tuberculosis, WQ-3810 might represent a new, potent anti-tuberculosis drug that can be effective even against FQ-resistant Mtb strains.
AB - Fluoroquinolone (FQ) resistance in Mycobacterium tuberculosis (Mtb), caused by amino acid substitutions in DNA gyrase, has been increasingly reported worldwide. WQ-3810 is a newly developed FQ that is highly active against FQ-resistant pathogens; however, its activity against Mtb has not been evaluated. Herein we examined the efficacy of WQ-3810 against Mtb through the use of recombinant Mtb DNA gyrases. In addition, in vitro antimycobacterial activity of WQ-3810 was evaluated against recombinant Mtb var. bovis Bacille Calmette–Guérin strains in which gyrase-coding genes were replaced with Mtb variants containing resistance-conferring mutations. WQ-3810 showed a higher inhibitory activity than levofloxacin against most recombinant DNA gyrases with FQ-resistance mutations. Furthermore, WQ-3810 showed inhibition even against a DNA gyrase variant harboring a G88C mutation which is thought to confer the highest resistance against FQs in clinical Mtb isolates. In contrast, the FQ susceptibility test showed that WQ-3810 had relatively weak mycobactericidal activity compared with moxifloxacin. However, the combination of WQ-3810 and ethambutol showed the greatest degree of synergistic activity against recombinant strains. Since FQs and ethambutol have been used in multi-drug therapy for tuberculosis, WQ-3810 might represent a new, potent anti-tuberculosis drug that can be effective even against FQ-resistant Mtb strains.
KW - Ethambutol
KW - Fluoroquinolone resistance
KW - gyrA mutations
KW - Mycobacterium tuberculosis
KW - Synergistic effect
KW - WQ-3810
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UR - http://www.scopus.com/inward/citedby.url?scp=85075273966&partnerID=8YFLogxK
U2 - 10.1016/j.tube.2019.101891
DO - 10.1016/j.tube.2019.101891
M3 - Article
C2 - 31778929
AN - SCOPUS:85075273966
SN - 1472-9792
VL - 120
JO - Bulletin of the International Union Against Tuberculosis and Lung Disease
JF - Bulletin of the International Union Against Tuberculosis and Lung Disease
M1 - 101891
ER -
