Department of Medical Innovations, New Drug Research Division, Otsuka Pharmaceutical Co., Ltd., Tokushima, Japan.
Division of Bioresources, International Institute for Zoonosis Control, Hokkaido University, Sapporo, Japan.
J Antimicrob Chemother. 2022 Nov 28;77(12):3248-3255. doi: 10.1093/jac/dkac308.
Enteric infections are a major public health issue in developing countries. Antimicrobial resistance is also a problem for enteric infection. OPS-2071 is a novel quinolone antibiotic with low oral absorption and potent antibacterial activity against Clostridioides difficile.
This study was conducted to confirm the antimicrobial activity of OPS-2071 against major enteropathogenic bacteria and to evaluate the risk of emergence of drug resistance.
The antibacterial activity was evaluated by the agar dilution method. The inhibitory activity against DNA gyrase and topoisomerase IV was determined by supercoiling assay and decatenation assay, respectively. The mutant prevention concentration and frequency of spontaneous resistance were determined by inoculation on drug-containing agar.
Compared with the reference drugs, the antibacterial activity of OPS-2071 was more potent against Gram-positive bacteria and Campylobacter jejuni, including quinolone-resistant strains. Against other Gram-negative bacteria, OPS-2071 was comparable to existing quinolones. The inhibitory activities against DNA gyrase with quinolone-resistant mutations closely correlated with the antibacterial activity. Spontaneous resistance to OPS-2071 was not observed in Staphylococcus aureus and Escherichia coli and was lower than that of existing quinolones and higher than that of azithromycin in C. jejuni. The mutant prevention concentration of OPS-2071 was lower than that of tested compounds in S. aureus and C. jejuni and slightly higher than that of existing quinolones in E. coli.
The broad and potent in vitro antibacterial activity and lower risk of drug resistance suggested that OPS-2071 may be useful for enteric infections caused by major pathogens including quinolone-resistant Campylobacter.
肠道感染是发展中国家的一个主要公共卫生问题。抗生素耐药性也是肠道感染的一个问题。OPS-2071 是一种新型的喹诺酮类抗生素，口服吸收低，对艰难梭菌具有强大的抗菌活性。
本研究旨在确认 OPS-2071 对主要肠道病原体的抗菌活性，并评估耐药性产生的风险。
采用琼脂稀释法评估抗菌活性。通过超螺旋化试验和解链试验分别测定对 DNA 回旋酶和拓扑异构酶 IV 的抑制活性。通过在含药琼脂上接种来测定突变预防浓度和自发耐药频率。
与参考药物相比，OPS-2071 对革兰氏阳性菌和空肠弯曲菌（包括耐喹诺酮菌株）的抗菌活性更强。对其他革兰氏阴性菌，OPS-2071 与现有的喹诺酮类药物相当。对具有喹诺酮耐药突变的 DNA 回旋酶的抑制活性与抗菌活性密切相关。金黄色葡萄球菌和大肠杆菌中未观察到对 OPS-2071 的自发耐药，其耐药率低于现有喹诺酮类药物，高于阿奇霉素在空肠弯曲菌中的耐药率。OPS-2071 的突变预防浓度在金黄色葡萄球菌和空肠弯曲菌中低于测试化合物，在大肠杆菌中略高于现有喹诺酮类药物。
OPS-2071 具有广泛而强大的体外抗菌活性，耐药风险较低，提示 OPS-2071 可能对包括耐喹诺酮空肠弯曲菌在内的主要病原体引起的肠道感染有用。
