Campylobacteriosis, primarily caused by Campylobacter spp. with C. jejuni being the predominant species, has emerged as a leading cause of global bacterial gastroenteritis [1]. Over the past decade, its incidence and prevalence have surged in both developed and developing countries, with significant public health implications [2,3]. Campylobacteriosis typically causes symptoms such as diarrhea, fever, stomach cramps and vomiting and often recovering without antibiotic treatment. However, in cases where the immune system is compromised, severe infections may persist, the treatment with antimicrobial drugs such as quinolones and macrolides are necessary [4].

Due to the escalating resistance to quinolones, the World Health Organization (WHO) has categorized Campylobacter as a priority pathogen on its list of antibiotic-resistant bacteria [5]. Consequently, there is a pressing need for research and the development of novel, effective drugs distinct from those currently in used. Quinolones resistance in bacteria can result from various mechanisms [6,7]. Notably, in Campylobacter, a predominant mechanism involves point mutations in the gyrA at the quinolone resistance-determining region (QRDR). Specifically, a single point mutation causing substitution of the 86th amino acid from threonine to isoleucine (T86I) is a common cause of quinolone-resistant C. jejuni [[8], [9], [10]]. Other mutations in the GyrA that confer resistance, such as Asp-90→Asn have been rarely reported [9].

WQ compounds represent a novel series of quinolones, designed to offer advancements over traditional quinolones by targeting bacterial DNA gyrase and topoisomerase IV with potentially enhanced efficacy and reduced resistance. Recently, WQ-3334, a novel quinolone and a member of WQ compounds, has been shown a potent inhibitory activity against several bacteria. It has shown particular efficacy against bacteria resistant to ciprofloxacin (CIP) and levofloxacin, such as Escherichia coli and Acinetobacter baumannii [11]. Additionally, it has been demonstrated heightened inhibitory potential in the DNA gyrase of Salmonella spp., Mycobacterium tuberculosis, and Mycobacterium leprae, particularly in cases with amino acid substitutions in GyrA [[12], [13], [14], [15]].

This study aims to elucidate the significant impact of substituents in WQ compounds by comparing WQ-3334, WQ-4064, and WQ-4065, which share similar structural features (Fig. 1).