Synthetic Peptide Derived from Scorpion Venom Displays Minimal Toxicity and Anti-infective Activity in an Animal Model

Abstract

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.

Advances of Antimicrobial Peptide‐Based Biomaterials for the Treatment of Bacterial Infections

“…In a mouse model of skin abrasion induced by A. baumannii , the peptide significantly reduced the bacterial load at infected tissue sites. [ 95 ] Similarly, Pse‐T2 was synthesized using a Lys substitution and truncation design based on the frog‐derived AMP Pseudin‐2. Wounds infected with MDR P. aeruginosa treated with Pse‐T2 healed significantly faster than untreated wounds or wounds treated with ciprofloxacin (Figure 8B).…”

Bacterial Infections and Cancer: Exploring This Association And Its Implications for Cancer Patients

“…A systematic analysis of bacteremia infections in cancer patients highlights that Staphylococcus aureus infections accounts for 1.3% to 12% of all bacteremia cases [ 112 ]. Infections caused by Staphylococcus aureus often reportedly led to BSIs, skin infections, pneumonia, and endocarditis [ 113 ]. Staphylococcus aureus is of clinical interest because the bacterium can form small colony variants (SCV) in addition to releasing virulence factors (e.g., enterotoxins and proteases) that interfere with the host’s innate immune response [ 114 , 115 ].…”

“…Patients infected with Acinetobacter baumannii have a significantly increased mortality rate of up to 80% [ 119 ]. Patients also develop complications from BSI, respiratory tract infections, meningitis, UTIs, and skin infections [ 113 , 120 ]. The pathogenesis of A. baumannii infection is severe because the bacterium can adapt to the host environment in several ways, which include the secretion of biofilms (thick polysaccharide capsules) and porins, alongside the release of enzymes and virulence factors.…”

“…Pseudomonas aeruginosa is an increasingly prevalent opportunistic pathogen that can cause serious and life-threatening nosocomial infections [ 116 ]. P. aeruginosa has been implicated in causing BSI, respiratory infections, and endocarditis [ 113 , 121 ]. The bacterium is highly adaptive to the host environment owing to its robust genome and its ability to form biofilms, activate a motile-sessility switch, and secrete secondary metabolites [ 122 ].…”

“…can also infect the respiratory tract, surgical wounds, the urinary tract, and the bloodstream of cancer patients [ 123 ]. These bacteria facilitate soft-tissue infections, BSIs, and endocarditis [ 113 ]. Often, the bacteria population thrives in its host environment through the use of flagellum, the formation of biofilms, and the secretion of endotoxins [ 124 ].…”