Design of Heptad Repeat Amphiphiles Based on Database Filtering and Structure-Function Relationships to Combat Drug-Resistant Fungi and Biofilms.

ABSTRACT

Due to the emergence of reports of multidrug-resistant fungi, infections caused by multidrug-resistant fungi and biofilms are considered to be a global threat to human health due to the lack of effective broad-spectrum drugs. Here, we developed a series heptad repeat sequences based on an antimicrobial peptide database (APD) and structure-function relationships. Among the developed peptides, the target peptide ACR3 exhibited good activity against all fungi and bacteria tested, including fluconazole-resistant Candida albicans (C. albicans) and methicillin-resistant Staphylococcu saureus (S. aureus), while demonstrating relatively low toxicity and good salt tolerance. The peptide ACR3 inhibits the formation of C. albicans biofilms and has a therapeutic effect on mature biofilms in vitro and in vivo. Moreover, we did not observe any resistance of C. albicans and E. coli against the peptide ACR3. A series of assays and microscopy were used to analyze the antimicrobial mechanism. These results showed that the antimicrobial activity of the peptide ACR3 utilizes a multimodal mechanism that degrades the cell wall barrier, alters the cytoplasmic membrane electrical potential, and induces intracellular reactive oxygen species (ROS) production. In general, the peptide ACR3 is a potent antibacterial agent that shows great potential for use in biomedical coatings and healthcare formulas to combat the growing threat of fungal and bacterial infection.