A novel synthetic peptide inspired on Lys49 phospholipase A 2 from Crotalus oreganus abyssus snake venom active against multidrug-resistant clinical isolates

Harnessing snake venom phospholipases A2 to novel approaches for overcoming antibiotic resistance

“…Peptide pC‐CoaTxII showed greater activity against Gram‐negative bacteria, although its effects against Gram‐positive bacteria were significant. Experimental results show pC‐CoaTx‐II to be more active against both ATCC and clinical drug‐resistant isolates, as compared to the parent protein (Almeida et al, ).…”

“…Though some studies have validated the antibacterial potential of C‐terminal region of Asp49 PLA 2 s (Costa et al, ), multiple studies have been carried out on Lys49 PLA 2 s, due to the independence of catalytic activity suggesting the presence of noncatalytic molecular regions capable of exerting different bioactivities. In this connection, Lomonte, Moreno, Tarkowski, Hanson, and Maccarana () demonstrated for the first time that biomimetic peptides replicate the effects of their parent svPLA 2 s. Since this pioneering study, many synthetic peptides based on the same molecular regions were evaluated for a better understanding of the mechanisms of myotoxic, antibacterial, antiviral, and antitumoral actions of Lys49 svPLA 2 s (Almeida et al, ; Gebrim et al, ; Lomonte et al, ). Therefore, these catalytically inactive toxins are taken as valuable templates for creation and innovation in antibiotherapy, building on smaller peptide segments with antibacterial potential (Figure ).…”

“…Several experimental and bioinformatics studies have addressed the unraveling of molecular mechanisms underpinning the antibacterial activity of small cationic peptides inspired in Lys49 svPLA 2 s (Almeida et al, ; Lomonte et al, ; Santos‐Filho et al, ). Interesting findings were made, although much more remain to be unveiled.…”

“…Subsequently, the molecular basis for the action of pC‐CoaTx‐I was investigated in silico. From this study, it was suggested that the peptide is inserted into the cell membrane, which then promotes the opening of water channels, with may either (a) cause an osmotic imbalance to bacterial cells leading to their disruption, or (b) interfere with the nonpolar interactions of the phospholipid bilayer, causing severe membrane destabilization and consequent bacterial death (Almeida et al, ).…”

“…For instance, it has already been mentioned that an increase in Trp content can improve antibacterial activity of Lys49 PLA 2 s‐derived AMPs; however, that was also found to potentiate toxicity against eukaryotic cells, meaning that a fine sequence tuning is required to ensure a favorable balance between activity and safety (Diniz‐Sousa et al, ; Santamaria, Larios, Angulo, et al, ). Insertion of positively charged residues as Lys to promote peptide accumulation onto the negatively charged membranes should be equally used with caution: while Lys residues promote formation of a hydrophilic patch eventually allowing water entrance and diffusion through the membrane, causing its destabilization (Almeida et al, ; Yu et al, ), they also make peptides more prone to proteolytic degradation (Arias et al, ).…”