WQ-3810: A new fluoroquinolone with a high potential against fluoroquinolone-resistant Mycobacterium tuberculosis. (January 2020)

• Record Type: Journal Article
• Authors: Ouchi, Yuki; Mukai, Tetsu; Koide, Kentaro; Yamaguchi, Tomoyuki; Park, Jong-Hoon; Kim, Hyun; Yokoyama, Kazumasa; Tamaru, Aki; Gordon, Stephen V.; Nakajima, Chie; Suzuki, Yasuhiko
• Is Part Of: Tuberculosis. Volume 120(2020)
• Publication Date: 2020-01
• Subjects: WQ-3810 -- Fluoroquinolone resistance -- gyrA mutations -- Mycobacterium tuberculosis -- Ethambutol -- Synergistic effect; 616.995
• DOI: 10.1016/j.tube.2019.101891
• Languages: English
• ISSNs: 1472-9792

Abstract

Abstract: 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.