Gomesin, a
disulfide-rich
antimicrobial peptide produced by the Brazilian spider Acanthoscurria gomesiana, has been shown to be potent against Gram-negative bacteria and to possess selective anticancer properties against
melanoma cells. In a recent study, a backbone cyclized analogue of
gomesin was shown to be as active but more stable than its native form. In the current study, we were interested in improving the antimicrobial properties of the cyclic
gomesin, understanding its selectivity toward
melanoma cells and elucidating its antimicrobial and anticancer mode of action. Rationally designed analogues of cyclic
gomesin were examined for their antimicrobial potency, selectivity toward
cancer cells, membrane-binding affinity, and ability to disrupt cell and model membranes. We improved the activity of cyclic
gomesin by ∼10-fold against tested Gram-negative and Gram-positive bacteria without increasing toxicity to human red blood cells. In addition, we showed that
gomesin and its analogues are more toxic toward
melanoma and
leukemia cells than toward red blood cells and act by selectively targeting and disrupting
cancer cell membranes. Preference toward some
cancer types is likely dependent on their different cell membrane properties. Our findings highlight the potential of
peptides as antimicrobial and anticancer leads and the importance of selectively targeting
cancer cell membranes for
drug development.