pH sensitive antimicrobial peptide with targeted activity in a mildly acidic microenvironment

Antimicrobial peptides (AMPs) are short peptides that can interact with the cellular membrane, which can actively inhibit the growth of diverse microorganisms. In recent years, AMPs have become a promising antimicrobial agent, however, the lack of selectivity and unwanted cytotoxicity of AMPs limit their development as therapeutic drugs. In this study, we employed a pH-sensitive histidine-glutamic acid (“HE”) peptide pro-sequence to modify an AMP, model amphipathic peptide (MAP), resulting in a pH-sensitive AMP termed HE-MAP. At bacterial infection sites, due to the inflammatory response and pathogen-host cell interactions, there is typically a mildly acidic pH. This microenvironment provides a unique recognition site for the selective distribution of HE-MAP. Under neutral pH, the HE pro-sequence can mask the cationic charge of MAP, therefore HE-MAP only exhibits its toxic function only under mildly acidic pH where the cationic charge is unmasked. The results from this study demonstrated that HE-MAP could specifically inhibit the growth of Escherichia coli (E. coli) and Acinetobacter baumannii (A. baumannii) under pH 6–6.5 and exhibited low cytotoxicity toward mammalian cells and erythrocytes at normal physiological pH 7.4. These results indicate that HE-MAP is potentially a new antimicrobial agent with pH sensitive selectivity.