Hubei Hongshan Laboratory, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, Hubei, China; State Key Laboratory of Agricultural Microbiology, Huazhong Agricultural University, Wuhan, Hubei, China.
Hubei Hongshan Laboratory, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, Hubei, China.
Biomed Pharmacother. 2022 Sep;153:113334. doi: 10.1016/j.biopha.2022.113334. Epub 2022 Jul 4.
The persistent incidence of high levels of multidrug-resistant (MDR) bacteria seriously endangers global public health. In response to MDR-associated infections, new antibacterial drugs and strategies are particularly needed. Screening to evaluate a potential compound to reverse antibiotic resistance is a good strategy to alleviate this crisis. In this paper, using high-throughput screening methods, we identified that oxyclozanide potentiated tetracycline antibiotics act against MDR bacterial pathogens by promoting intracellular accumulation of tetracycline in resistant bacteria. Furthermore, mechanistic studies demonstrated that oxyclozanide could directly kill bacteria by disrupting bacterial membrane and inducing the overproduction of bacterial reactive oxygen species. Oxyclozanide effectively reduced the production of virulence proteins in S. aureus and neutralized the produced α-hemolysin, thereby effectively alleviating the inflammatory response caused by bacteria. Finally, oxyclozanide significantly reversed tetracycline resistance in animal infection assays. In summary, these results demonstrated the capacity of oxyclozanide as a novel antibiotic adjuvant, antibacterial and anti-virulence multifunctional compound to circumvent MDR bacteria and improve the therapeutic effect of persistent infections caused by MDR bacteria worldwide.
高水平耐多药（MDR）细菌的持续发生严重威胁着全球公共健康。针对 MDR 相关感染，特别需要新的抗菌药物和策略。筛选以评估一种潜在的化合物来逆转抗生素耐药性是缓解这一危机的良好策略。在本文中，我们使用高通量筛选方法，发现奥硝唑增强四环素类抗生素通过促进耐药菌细胞内四环素的积累来对抗 MDR 细菌病原体。此外，机制研究表明，奥硝唑可以通过破坏细菌膜并诱导细菌活性氧的过度产生来直接杀死细菌。奥硝唑有效降低了金黄色葡萄球菌中毒力蛋白的产生，并中和了产生的α-溶血素，从而有效缓解了细菌引起的炎症反应。最后，奥硝唑在动物感染实验中显著逆转了四环素的耐药性。总之，这些结果表明奥硝唑具有作为一种新型抗生素佐剂、抗菌和抗毒多功能化合物的潜力，可规避 MDR 细菌并提高全球由 MDR 细菌引起的持续性感染的治疗效果。
