Antimicrobial Peptides Incorporating Halogenated Marine-Derived Amino Acid Substituents

Abstract

Small synthetic mimics of cationic antimicrobial peptides represent a promising class of compounds with leads in clinical development for the treatment of persistent microbial infections. The activity and selectivity of these compounds rely on a balance between hydrophobic and cationic components, and here, we explore the activity of 19 linear cationic tripeptides against five different pathogenic bacteria and fungi, including clinical isolates. The compounds incorporated modified hydrophobic amino acids inspired by motifs often found in bioactive marine secondary metabolites in combination with different cationic residues to probe the possibility of generating active compounds with improved safety profiles. Several of the compounds displayed high activity (low μM concentrations), comparable with the positive controls AMC-109, amoxicillin, and amphotericin B. A higher activity was observed against the fungal strains, and a low in vitro off-target toxicity was observed against erythrocytes and HeLa cells, thereby illustrating effective means for tuning the activity and selectivity of short antimicrobial peptides.

Engineering the interaction of short antimicrobial peptides with bacterial barriers

“…79 Similar building blocks are generally used in synthetic halogenated AMPs, leading to an increase of the hydrophobic volume of Phe and Trp residues. 73 Molchanova et al demonstrated that inactive peptoids can be converted into effective antibacterials by bromination of Phe residues without leading to increased haemolytic activity or in vitro cytotoxicity. 74 Similarly, a study by Jia et al evidenced the improved proteolytic stability of several halogenated derivatives of the honeybee peptide Jelleine-1 (PFKLSLHL-NH 2 ), with the iodinated analogue displaying an eightfold increase in the antimicrobial activity with respect to the parent peptide.…”

Creating New Antifoulants Using the Tools and Tactics of Medicinal Chemistry

“…Compounds produced by vertebrate innate immune systems have been studied and optimized to generate truncated mimics with potential medical and antifouling applications . Small synthetic mimics of antimicrobial peptides, decorated with unnatural cationic and hydrophobic amino acids, have been shown to maintain the activity of the native defense protein counterparts. − We have explored a selection of linear tripeptides in an aqueous environment to assess their potential effect on the different stages of the biofouling process . Perhaps unexpectedly, we demonstrated that short peptidomimetics are highly efficient against the growth and adhesion of marine bacteria and barnacles.…”