Host defense antimicrobial peptides as antibiotics: design and application strategies

Abstract

This review deals with the design and application strategies of new antibiotics based on naturally occurring antimicrobial peptides (AMPs). The initial candidate can be designed based on three-dimensional structure or selected from a library of peptides from natural or laboratory sources followed by optimization via structure-activity relationship studies. There are also advanced application strategies such as induction of AMP expression from host cells by various factors (e.g., metals, amino acids, vitamin D and sunlight), the use of engineered probiotic bacteria to deliver peptides, the design of prodrug and peptide conjugates to improve specific targeting. In addition, combined uses of newly developed AMPs with existing antimicrobial agents may provide a practical avenue for effective management of antibiotic-resistant bacteria (superbugs), including biofilms. Finally, we highlight AMPs already in use or under clinical trials.

Figure 1. Antimicrobial peptides (a–c) and their timeline of applications (d)

The amphipathic and cationic antimicrobial peptide (a) preferentially binds to anionic bacterial membranes (b) rather than mammalian cell membranes, consisting of phosphatidylcholines (yellow) and cholesterol (square) with minor anionic lipid (blue) in the inner leaf (i) of the bilayer (c). The NMR structure of the major antimicrobial region (residues 17–32) of human cathelicidin LL-37 (a) is used to illustrate the amphipathic feature [14]. In the cartoon view of bacterial inner membranes (b), E. coli is assumed with 30% anionic phophatidylglycerols (black) and 70% phosphatidylethanolamines (orange). (d) Select AMPs in use (orange, top) or under clinical trials (blue, bottom) are depicted. Further examples can be viewed in Table 2.

Figure 2. Application strategies of antimicrobial peptides

(a) prodrug; (b) conjugation; (c) combined use; (d) induction from the host; and (e) the use of probiotic bacteria to deliver and express the needed antimicrobial peptides. See the text for further details.