Tissue damage alleviation and mucin inhibition by P5 in a respiratory infection mouse model with multidrug-resistant Acinetobacter baumannii

Although the discovery of antibiotics has made significant positive contributions to public health and medicine, it now poses a serious threat due to the increasing antibiotic resistance in various bacteria. Carbapenem-resistant and multidrug-resistant (MDR) Acinetobacter baumannii is spreading globally, exacerbating respiratory diseases such as chronic obstructive pulmonary disease and cystic fibrosis. Antimicrobial peptides (AMPs), with broad antibacterial activity, have emerged as promising alternatives for treating MDR A. baumannii infections. The AMP P5 exhibits strong antibacterial and anti-biofilm activities against MDR A. baumannii strains isolated from patients. Compared to colistin, a commonly used antibiotic for MDR A. baumannii infections, P5 has a lower potential for inducing drug resistance. Additionally, P5 displays stability in human serum and minimal cytotoxicity in human cell lines. P5 not only suppressed the overexpression of pro-inflammatory cytokines and inflammatory transcription factors in lung epithelial cells (A549) and in a mouse model of respiratory infection but also alleviated lung tissue damage caused by infection. Moreover, P5 effectively alleviated excessive mucin secretion in vitro and in vivo by inhibiting inflammatory transcription factors, epidermal growth factor receptor, and signal transducer and activator of transcription 3-key regulators of mucin expression, a hallmark of inflammatory respiratory diseases. These findings highlight the therapeutic potential of P5 in treating MDR A. baumannii infections and associated inflammatory respiratory conditions.