抗耐药菌红霉素的结构修饰策略、构效关系及全合成研究进展

As clinically important and widely used drugs, macrolide antibiotics exhibit broad-spectrum antimicrobial properties and excellent therapeutic efficacy, such as erythromycin, clarithromycin and azithromycin, all of which are essential medicines recommended by the World Health Organization (WHO). However, the emergence of bacterial resistance has significantly reduced their antibacterial efficacy, leaving the treatment of numerous diseases facing a dilemma of no effective drugs available. In particular, macrolide antibiotics, the 3rd-generation telithromycin and the 4th-generation solithromycin included, are difficult to exert therapeutic effects against infectious diseases caused by constitutive erm-carrying Staphylococcus aureus, constitutive erm-carrying Streptococcus pyogenes, and Mycoplasma pneumoniae with A2058 mutation. To overcome the problem of bacterial resistance to macrolide antibiotics and further enhance their antibacterial activity against drug-resistant bacteria, extensive studies have been performed on new structures. Taking the development history of macrolide antibiotics as a chronological framework, the research progress of these drugs against drug-resistant bacteria from 2013 to 2024 is systematically summarized. This study focuses on elaborating the structure-activity relationships of new structures, pharmacokinetic characteristics, and total synthesis strategies of non-natural macrolides, and summarizes the key breakthroughs of 5th-generation macrolide antibiotics in combating bacterial resistance. This review will provide guidance for subsequent drug design, research on resistance mechanisms, and the development of novel antibacterial strategies.