Azithromycin Derivatives for Overcoming Antibacterial Resistance: Structural Modification and Structure–Activity Relationships

Antimicrobial resistance has significantly compromised the therapeutic efficacy of many antibiotics, highlighting the need for new agents capable of overcoming bacterial resistance. The discovery of antibiotics in the early 20th century contributed significantly to transforming modern medicine and saved countless lives. However, the alarming increase in antibiotic resistance now threatens these achievements. The misuse and overuse of antibiotics have driven the continuous evolution and adaptation of microorganisms, contributing to this growing global health challenge. Azithromycin (AZM), a widely used macrolide antibiotic with favorable pharmacokinetic properties, is increasingly affected by resistance mechanisms. A number of researchers have therefore designed and developed AZM derivatives with promising antibacterial properties. This review summarizes advances in the structural modification of AZM, focusing on side-chain modification, heterocyclic substitution, molecular hybridization, and their associated structure–activity relationships. Selected derivatives demonstrated enhanced activity against resistant bacterial pathogens compared with AZM, although activity varies according to substituent position, linker structure, and overall molecular properties. Nevertheless, the activity of many AZM derivatives against Gram-negative organisms remains limited, with restricted outer-membrane permeability and inadequate intracellular accumulation representing important barriers to achieving effective antibacterial activity. Overall, the structural modification of AZM represents a promising strategy for developing potential antibacterial agents, but further pharmacological and in vivo studies are required to establish their therapeutic potential.