Discovery of lipidated cysteine-based amphiphiles as bioinspired antimicrobial peptidomimetics against drug-resistant bacteria.

The emergence of multidrug-resistant bacteria poses a significant threat to modern medical practices and human health, creating an urgent demand for novel antibacterial agents. Inspired by host-defense peptides (HDPs), herein we employed fatty acid acylation to fine-tune the amphiphilic balance of cysteine-based amphiphilic compounds, synthesizing a series of antimicrobial peptidomimetics and evaluating their antimicrobial activity. Among them, 10c stood out due to its broad-spectrum antimicrobial activity against both Gram-positive and Gram-negative bacteria, as well as its low hemolytic activity. Like HDPs, it rapidly killed bacteria primarily via a membrane-disruptive action mode, with a low propensity to induce bacterial resistance. Additionally, its ease of synthesis, serum stability, and ability to address some of the challenges HDPs face in different physiological conditions may enhance its clinical applications. Importantly, 10c demonstrated significant therapeutic potential in mouse models of MRSA-induced pneumonia and keratitis. Overall, the present study provides new therapeutic strategies and identifies a potential lead compound for addressing antibiotic-resistant bacteria, offering novel insights for the development of next-generation antibacterial agents.