Expanding the antimicrobial spectrum of lugdunin: Discovery of multi-cationic derivatives of lugdunin with antimicrobial activity against gram-positive and gram-negative bacteria.

Lugdunin, a newly discovered antibiotic with a unique structure, emerged during a decade-long antibiotic discovery void and is considered a promising lead for combating drug-resistant bacteria. However, its narrow spectrum targeting only Gram-positive bacteria and its structural limitations have hindered its development and clinical application. Herein, inspired by our previous combinatorial modification strategies for lugdunin, we designed and synthesized a series of multi-cationic lugdunin derivatives using a biphenylmethyl modification on the tryptophan indole structure combined with multi-cationic amino acid mutations, aiming to expand its antimicrobial spectrum. Our results showed that the optimized derivative, Lug-15, exhibited strong antibacterial activity against both Gram-positive and Gram-negative bacteria, including Escherichia coli and Pseudomonas aeruginosa. Lug-15 rapidly kills bacteria primarily through membrane disruption and had a very low propensity to induce bacterial resistance. Additionally, it demonstrated low hemolytic toxicity and significant therapeutic potential in various infection models, including keratitis caused by MRSA and P. aeruginosa, MRSA-induced pneumonia, thigh muscle infection, and wound infection, indicating Lug-15's broad-spectrum therapeutic potential. Therefore, this study overcomes the historical limitation of prior SAR attempts and offers a new lead for combating drug-resistant bacteria.