Novel High-Efficacy Antimicrobial Peptides Derived from Myxinidin and their Therapeutic Efficacy in Bacterial Pneumonia.

Myxinidin is a natural antimicrobial peptide with a short sequence and low inherent toxicity, though its activity remains suboptimal for clinical application. To overcome this limitation, we performed rational modifications by substituting key residues to stabilize the α-helical conformation while increasing hydrophobicity and net positive charge. Among the designed analogs, M14 and M21 exhibited potent broad-spectrum activity against all tested bacterial strains, along with high selectivity for bacterial over mammalian cells. Both peptides demonstrated significant therapeutic efficacy in a mouse model of E. coli-induced pneumonia, acting primarily through rapid bacterial membrane disruption. Additionally, M14 and M21 displayed favorable safety profiles in vivo. Collectively, these findings identify M14 and M21 as promising candidates for the development of novel therapeutic agents against bacterial pneumonia.