Effect of WQ-3334 on Campylobacter jejuni carrying a DNA gyrase with dominant amino acid substitutions conferring quinolone resistance

Nami Miura-Ajima; Pondpan Suwanthada; Siriporn Kongsoi; Hyun Kim; Ruttana Pachanon; Kentaro Koide; Shigetarou Mori; Jeewan Thapa; Chie Nakajima; Yasuhiko Suzuki

doi:10.1016/j.jiac.2024.04.002

Effect of WQ-3334 on Campylobacter jejuni carrying a DNA gyrase with dominant amino acid substitutions conferring quinolone resistance

J Infect Chemother. 2024 Apr 4:S1341-321X(24)00110-7. doi: 10.1016/j.jiac.2024.04.002. Online ahead of print.

Authors

Affiliations

¹ Division of Bioresources, Hokkaido University International Institute for Zoonosis Control, Sapporo, 001-0020, Japan.
² Faculty of Veterinary Medicine, Kasetsart University, Thailand.
³ Department of Bacteriology II, National Institute of Infectious Diseases, Musashi-Murayama, Tokyo, 208-0011, Japan.
⁴ Division of Bioresources, Hokkaido University International Institute for Zoonosis Control, Sapporo, 001-0020, Japan; International Collaboration Unit, Hokkaido University International Institute for Zoonosis Control, Sapporo, 001-0020, Japan; Hokkaido University Institute for Vaccine Research and Development, Sapporo, 001-0020, Japan.
⁵ Division of Bioresources, Hokkaido University International Institute for Zoonosis Control, Sapporo, 001-0020, Japan; International Collaboration Unit, Hokkaido University International Institute for Zoonosis Control, Sapporo, 001-0020, Japan; Hokkaido University Institute for Vaccine Research and Development, Sapporo, 001-0020, Japan. Electronic address: suzuki@czc.hokudai.ac.jp.

PMID: 38580055
DOI: 10.1016/j.jiac.2024.04.002

Abstract

Introduction: Campylobacteriosis stands as one of the most frequent bacterial gastroenteritis worldwide necessitating antibiotic treatment in severe cases and the rise of quinolones-resistant Campylobacter jejuni poses a significant challenge. The predominant mechanism of quinolones-resistance in this bacterium involves point mutations in the gyrA, resulting in amino acid substitution from threonine to isoleucine at 86th position, representing more than 90% of mutant DNA gyrase, and aspartic acid to asparagine at 90th position. WQ-3334, a novel quinolone, has demonstrated strong inhibitory activity against various bacteria. This study aims to investigate the effectiveness of WQ-3334, and its analogues, WQ-4064 and WQ-4065, with a unique modification in R1 against quinolones-resistant C. jejuni.

Methods: The structure-activity relationship of the examined drugs was investigated by measuring IC₅₀ and their antimicrobial activities were accessed by MIC against C. jejuni strains. Additionally, in silico docking simulations were carried out using the crystal structure of the Escherichia coli DNA gyrase.

Result: WQ-3334 exhibited the lowest IC₅₀ against WT (0.188 ± 0.039 mg/L), T86I (11.0 ± 0.7 mg/L) and D90 N (1.60 ± 0.28 mg/L). Notably, DNA gyrases with T86I substitutions displayed the highest IC₅₀ values among the examined WQ compounds. Moreover, WQ-3334 demonstrated the lowest MICs against wild-type and mutant strains. The docking simulations further confirmed the interactions between WQ-3334 and DNA gyrases.

Conclusion: WQ-3334 with 6-amino-3,5-difluoropyridine-2-yl at R1 severed as a remarkable candidate for the treatment of foodborne diseases caused by quinolones-resistant C. jejuni as shown by the high inhibitory activity against both wild-type and the predominant quinolones-resistant strains.

Keywords: Antimicrobial resistance; Campylobacter jejuni; DNA gyrase; Quinolones; WQ-3334.

Copyright © 2024 Japanese Society of Chemotherapy, Japanese Association for Infectious Diseases, and Japanese Society for Infection Prevention and Control. Published by Elsevier Ltd. All rights reserved.