Multidrug-resistant bacteria represent
a global health problem
increasingly leading to infections that are untreatable with our existing
antibiotic arsenal. Therefore, it is critical to identify novel effective
antimicrobials. Venoms represent an underexplored source of potential
antibiotic molecules. Here, we engineered a peptide (IsCT1-NH2) derived from the venom of the scorpion Opisthacanthus
madagascariensis, whose application as an antimicrobial had
been traditionally hindered by its high toxicity. Through peptide
design and the knowledge obtained in preliminary studies with single
and double-substituted analogs, we engineered IsCT1 derivatives with
multiple amino acid substitutions to assess the impact of net charge
on antimicrobial activity and toxicity. We demonstrate that increased
net charge (from +3 to +6) significantly reduced toxicity toward human
erythrocytes. Our lead synthetic peptide, [A]1[K]3[F]5[K]8-IsCT1-NH2 (net charge of
+4), exhibited increased antimicrobial activity against Gram-negative
and Gram-positive bacteria in vitro and enhanced
anti-infective activity in a mouse model. Mechanism of action studies
revealed that the increased antimicrobial activity of our lead molecule
was due, at least in part, to its enhanced ability to permeabilize
the outer membrane and depolarize the cytoplasmic membrane. In summary,
we describe a simple method based on net charge tuning to turn highly
toxic venom-derived peptides into viable therapeutics.
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