Antimicrobial Peptides Incorporating Halogenated Marine-Derived Amino Acid Substituents

ACS Med Chem Lett. 2023 May 4;14(6):802-809. doi: 10.1021/acsmedchemlett.3c00093.

Alexander J Craig ¹ ², Yuri Ermolovich ³, Alan Cameron ⁴, Agnes Rodler ⁵, Helen Wang ⁶, Jeffrey A Hawkes ², Madlen Hubert ⁵, Fredrik Björkling ³, Natalia Molchanova ⁷, Margaret A Brimble ⁴, Lindon W K Moodie ¹ ⁸, Johan Svenson ⁹

Affiliations

1 Drug Design and Discovery, Department of Medicinal Chemistry, Biomedical Centre, Uppsala University, 75123 Uppsala, Sweden.
2 Analytical Chemistry, Department of Chemistry, Biomedical Centre, Uppsala University, 75123 Uppsala, Sweden.
3 Department of Drug Design and Pharmacology, University of Copenhagen, DK-2100 Copenhagen, Denmark.
4 School of Chemical Sciences, University of Auckland, 23 Symonds Street, Auckland 1010, New Zealand.
5 Department of Pharmacy, Biomedical Centre, Uppsala University, 75123 Uppsala, Sweden.
6 Department of Medical Biochemistry and Microbiology, Biomedical Centre, Uppsala University, 75123 Uppsala, Sweden.
7 The Molecular Foundry, Lawrence Berkeley National Laboratory, Berkeley, California 94720, United States.
8 Uppsala Antibiotic Centre, Biomedical Centre, Uppsala University, 75123 Uppsala, Sweden.
9 Cawthron Institute, 98 Halifax Street East, Nelson 7010, New Zealand.

PMID: 37312845 DOI: 10.1021/acsmedchemlett.3c00093

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.

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