AMP-36 exhibits potent therapeutic efficacy against MRSA pneumonia through membrane-target mechanism.

The rapid emergence of multidrug-resistant (MDR) bacteria poses a critical challenge in hospital-acquired infections, particularly methicillin-resistant Staphylococcus aureus (MRSA) pneumonia. Antimicrobial peptides (AMPs) are promising therapeutic candidates due to their broad-spectrum antibacterial activity. Here, we report AMP-36, a 36-amino acid antimicrobial peptide rationally designed and synthesized from SAAP-148, exhibits potent antibacterial activity. AMP-36 displayed low micromolar minimum inhibitory concentrations and rapid bactericidal activity in vitro, achieving near-complete bacterial killing within 8 h. In the murine pneumonia model, AMP-36 significantly reduced bacterial burden in bronchoalveolar lavage fluid (BALF) and markedly alleviated lung inflammation. Scanning electron microscopy (SEM) revealed pronounced disruption of MRSA cell membranes following AMP-36 treatment, indicating membrane damage as the primary antibacterial mechanism. Transcriptomic analysis further demonstrated its broad transcriptional alterations. Collectively, these findings highlight AMP-36 as a promising therapeutic candidate for MRSA pneumonia and provide mechanistic insights into its antimicrobial action.