Breaking the Resistance: Next‐Generation Macrolide and Peptide Antibiotics

ABSTRACT

As conventional antibiotics are becoming less effective because of the rapid development of bacterial resistance, modifying existing antibiotic scaffolds has become an important approach for discovering new antimicrobial agents. This review summarizes recent advances in the structural modification of macrolides and antimicrobial peptides (AMPs). It describes the shift from semi synthetic methods to total and convergent synthesis, which has enabled the development of new macrolide derivatives with reduced susceptibility to ribosomal methylation and efflux pump‐mediated resistance. The review also highlights the modular assembly of macrolide subunits and the incorporation of non‐natural amino acids into peptide sequences to improve their stability against proteolytic degradation. In addition, the structure‐activity relationship (SAR) of these new analogues is discussed to explain how rational molecular design and organic synthesis are being used to improve the antibacterial activity of macrolides and AMPs against multidrug‐resistant (MDR) pathogens.