Feng Jin, Zheng Youle, Ma Wanqing, Ihsan Awais, Hao Haihong, Cheng Guyue, Wang Xu
National Reference Laboratory of Veterinary Drug Residues (HZAU) and MAO Key Laboratory for Detection of Veterinary Drug Residues, Huazhong Agricultural University, Wuhan, Hubei 430070, China.
MAO Laboratory for Risk Assessment of Quality and Safety of Livestock and Poultry Products, Huazhong Agricultural University, Wuhan, Hubei 430070, China.
Pharmacol Ther. 2023 Oct 28:108550. doi: 10.1016/j.pharmthera.2023.108550.
The rise of antibiotic resistance and the decrease in the discovery of new antibiotics have caused a global health crisis. Of particular concern is the fact that despite efforts to develop new antibiotics, drug discovery is unable to keep up with the rapid development of resistance. This ongoing crisis highlights the fact that single-target drugs may not always exhibit satisfactory therapeutic effects and are prone to target mutations and resistance due to the complexity of bacterial mechanisms. Retrospective studies have shown that most successful antibiotics have multiple targets. Compared with single-target drugs, successfully designed multitarget drugs can simultaneously regulate multiple targets to reduce resistance caused by single-target mutations or expression changes. In addition to a lower risk of drug-drug interactions, multitarget drugs show superior pharmacokinetics and higher patient compliance compared with combination therapies. Therefore, to reduce resistance, many efforts have been made to discover and design multitarget drugs with different chemical structures and functions. Although there have been numerous studies on how to develop drugs and slow down the development of drug resistance, the reduction of bacterial resistance by multitarget antibacterial drugs has not received widespread attention and is rarely mentioned in the peer-reviewed literature. This review summarises the development of antibiotic resistance and the mechanisms proposed for its emergence, examines the potential of multitarget drugs as an effective strategy to slow the development of resistance, and discusses the rationale for multitarget drug therapy. We also describe multitarget antibacterial compounds with the potential to reduce drug resistance and the available strategies to develop multitarget drugs.
抗生素耐药性的上升以及新抗生素发现数量的减少引发了一场全球健康危机。特别令人担忧的是，尽管人们努力研发新抗生素，但药物研发仍无法跟上耐药性的快速发展。这场持续的危机凸显了一个事实，即单靶点药物可能并不总是具有令人满意的治疗效果，并且由于细菌机制的复杂性，容易出现靶点突变和耐药性。回顾性研究表明，大多数成功的抗生素都有多个靶点。与单靶点药物相比，成功设计的多靶点药物可以同时调节多个靶点，以降低由单靶点突变或表达变化引起的耐药性。除了药物相互作用风险较低外，与联合疗法相比，多靶点药物还表现出更优的药代动力学和更高的患者依从性。因此，为了降低耐药性，人们做出了许多努力来发现和设计具有不同化学结构和功能的多靶点药物。尽管关于如何开发药物以及减缓耐药性发展已有大量研究，但多靶点抗菌药物对细菌耐药性的降低尚未得到广泛关注，在同行评审文献中也很少被提及。本综述总结了抗生素耐药性的发展及其出现的机制，探讨了多靶点药物作为减缓耐药性发展的有效策略的潜力，并讨论了多靶点药物治疗的基本原理。我们还描述了具有降低耐药性潜力的多靶点抗菌化合物以及开发多靶点药物的可用策略。
