WQ-3810: A new fluoroquinolone with a high potential against fluoroquinolone-resistant Mycobacterium tuberculosis

Yuki Ouchi; Tetsu Mukai; Kentaro Koide; Tomoyuki Yamaguchi; Jong-Hoon Park; Hyun Kim; Kazumasa Yokoyama; Aki Tamaru; Stephen V Gordon; Chie Nakajima; Yasuhiko Suzuki

doi:10.1016/j.tube.2019.101891

WQ-3810: A new fluoroquinolone with a high potential against fluoroquinolone-resistant Mycobacterium tuberculosis

Tuberculosis (Edinb). 2020 Jan:120:101891. doi: 10.1016/j.tube.2019.101891. Epub 2019 Nov 18.

Authors

Affiliations

¹ Division of Bioresources, Hokkaido University Research Center for Zoonosis Control, Kita 20 Nishi 10, Kita-ku, Sapporo, Hokkaido, 001-0020, Japan.
² Department of Mycobacteriology, Leprosy Research Center, National Institute of Infectious Diseases, 4-2-1 Aoba, Higashi-Murayama, Tokyo, 189-0002, Japan.
³ Laboratory of Tuberculosis Control, Department of Bacteriology II, National Institute of Infectious Diseases, 4-7-1 Gakuen, Musashi-Murayama, Tokyo, 208-0011, Japan.
⁴ Central Research Laboratory, Kissei Pharmaceutical Co., Ltd, 4365-1 Kashiwabara, Hotaka, Azumino, Nagano, 399-8304, Japan.
⁵ Department of Microbiology, Osaka Institute of Public Health, 1-3-69 Nakamichi, Higashinari-ku, Osaka, Osaka, 523-0025, Japan.
⁶ UCD School of Veterinary Medicine, University College Dublin, Dublin, D04 W6F6, Ireland; Global Institution for Collaborative Research and Education, Hokkaido University, Kita 20 Nishi 10, Kita-ku, Sapporo, Hokkaido, 001-0020, Japan.
⁷ Division of Bioresources, Hokkaido University Research Center for Zoonosis Control, Kita 20 Nishi 10, Kita-ku, Sapporo, Hokkaido, 001-0020, Japan; Global Institution for Collaborative Research and Education, Hokkaido University, Kita 20 Nishi 10, Kita-ku, Sapporo, Hokkaido, 001-0020, Japan.
⁸ Division of Bioresources, Hokkaido University Research Center for Zoonosis Control, Kita 20 Nishi 10, Kita-ku, Sapporo, Hokkaido, 001-0020, Japan; Global Institution for Collaborative Research and Education, Hokkaido University, Kita 20 Nishi 10, Kita-ku, Sapporo, Hokkaido, 001-0020, Japan. Electronic address: suzuki@czc.hokudai.ac.jp.

PMID: 31778929
DOI: 10.1016/j.tube.2019.101891

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.

Keywords: Ethambutol; Fluoroquinolone resistance; Mycobacterium tuberculosis; Synergistic effect; WQ-3810; gyrA mutations.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antibiotics, Antitubercular / pharmacology*
Azetidines / pharmacology*
Bacterial Proteins / genetics
Bacterial Proteins / metabolism*
DNA Gyrase / genetics
DNA Gyrase / metabolism*
Drug Resistance, Bacterial* / genetics
Drug Synergism
Drug Therapy, Combination
Ethambutol / pharmacology
Fluoroquinolones / pharmacology*
Microbial Sensitivity Tests
Mutation
Mycobacterium bovis / drug effects*
Mycobacterium bovis / enzymology
Mycobacterium bovis / growth & development
Mycobacterium tuberculosis / drug effects*
Mycobacterium tuberculosis / enzymology
Mycobacterium tuberculosis / genetics
Topoisomerase II Inhibitors / pharmacology*

Substances

Antibiotics, Antitubercular
Azetidines
Bacterial Proteins
Fluoroquinolones
Topoisomerase II Inhibitors
WQ-3810
Ethambutol
DNA Gyrase