The Spectrum of Design Solutions for Improving the Activity-Selectivity Product of Peptide Antibiotics against Multidrug-Resistant Bacteria and Prostate Cancer PC-3 Cells

• Published in: Molecules (Basel, Switzerland) Switzerland), 2020-08, Vol.25 (15), p.3526
• Main Authors: Juretić, Davor, Golemac, Anja, Strand, Denise E, Chung, Keshi, Ilić, Nada, Goić-Barišić, Ivana, Pellay, François-Xavier
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; Amino Acid Substitution; Animals; Anti-Bacterial Agents - chemistry; Anti-Bacterial Agents - pharmacology; Antibiotics, Antineoplastic - chemistry; Antibiotics, Antineoplastic - pharmacology; anticancer peptides; Antimicrobial Cationic Peptides - chemistry; Antimicrobial Cationic Peptides - pharmacology; antimicrobial peptides; Bacteria - drug effects; Cell-Penetrating Peptides - chemistry; Cell-Penetrating Peptides - pharmacology; design solutions; Drug Design; Drug Resistance, Multiple, Bacterial; Hemolysis - drug effects; Humans; Male; PC-3 Cells; Prostatic Neoplasms - drug therapy; Protein Engineering; selectivity; Structure-Activity Relationship; therapeutic index
• ISSN: 1420-3049; 1420-3049
• DOI: 10.3390/molecules25153526

The link between the antimicrobial and anticancer activity of peptides has long been studied, and the number of peptides identified with both activities has recently increased considerably. In this work, we hypothesized that designed peptides with a wide spectrum of selective antimicrobial activity will also have anticancer activity, and tested this hypothesis with newly designed peptides. The spectrum of peptides, used as partial or full design templates, ranged from cell-penetrating peptides and putative bacteriocin to those from the simplest animals (placozoans) and the Chordata phylum (anurans). We applied custom computational tools to predict amino acid substitutions, conferring the increased product of bacteriostatic activity and selectivity. Experiments confirmed that better overall performance was achieved with respect to that of initial templates. Nine of our synthesized helical peptides had excellent bactericidal activity against both standard and multidrug-resistant bacteria. These peptides were then compared to a known anticancer peptide polybia-MP1, for their ability to kill prostate cancer cells and dermal primary fibroblasts. The therapeutic index was higher for seven of our peptides, and anticancer activity stronger for all of them. In conclusion, the peptides that we designed for selective antimicrobial activity also have promising potential for anticancer applications.