Myxinidin-derived peptides **M14** and **M21** potently treat bacterial pneumonia by membrane disruption.

The escalating crisis of antimicrobial resistance (AMR) necessitates novel therapeutic strategies beyond conventional antibiotics. Bacterial pneumonia remains a leading cause of morbidity and mortality, often complicated by drug-resistant pathogens. Antimicrobial peptides (AMPs) offer a promising alternative due to their diverse mechanisms, frequently involving direct bacterial membrane disruption, which can circumvent established resistance pathways. However, natural AMPs like myxinidin often exhibit suboptimal activity, limited stability, or potential toxicity, hindering their clinical translation. This study addresses these limitations by rationally designing enhanced myxinidin analogs.

Researchers performed rational modifications on the natural antimicrobial peptide myxinidin, specifically substituting key residues to enhance its α-helical conformation, increase hydrophobicity, and boost net positive charge. Among the designed analogs, M14 and M21 were selected for further evaluation. Their broad-spectrum antimicrobial activity was assessed against various bacterial strains, alongside their selectivity for bacterial over mammalian cells. Therapeutic efficacy was then investigated in a mouse model of E. coli-induced pneumonia. The primary endpoint was the reduction of bacterial load and improvement of disease parameters, with an additional focus on their in vivo safety profiles.

The rationally designed myxinidin analogs, M14 and M21, exhibited potent broad-spectrum antimicrobial activity, effectively targeting all tested bacterial strains. Crucially, these peptides demonstrated high selectivity, preferentially acting against bacterial cells while sparing mammalian cells, indicating a favorable safety margin. In a mouse model of E. coli-induced pneumonia, both M14 and M21 showed significant therapeutic efficacy, substantially mitigating the infection. The primary mechanism of action was identified as rapid bacterial membrane disruption, leading to swift bacterial eradication. Furthermore, the peptides displayed favorable safety profiles in vivo, with no significant adverse effects observed. > M14 and M21 effectively disrupted bacterial membranes, providing a rapid and potent mechanism against diverse bacterial strains, including those causing pneumonia.