Abstract
Lipopeptides (LPs) have evolved from naturally occurring compounds to key therapeutic agents against multidrug-resistant (MDR) bacterial infections. However, their expanding clinical use has triggered emerging resistance mechanisms, posing serious challenges to anti-infective therapy. This systematic review outlines the development of LP resistance and highlights innovative strategies to counteract it. To overcome these evolving barriers, the field has transitioned from traditional empirical optimization to multidimensional rational design. Moving beyond conventional structure-activity relationship (SAR)-guided chemical synthesis, current approaches integrate diverse innovative methodologies. Based on these advances, this review provides the first systematic summary of contemporary strategies for developing novel LPs, offering new perspectives and methodological support to combat resistant bacterial infections and accelerate the development of next-generation LP-based therapeutics.