Snake Venom Cathelicidins as Natural Antimicrobial Peptides

Abstract

Bioactive small molecules isolated from animals, plants, fungi and bacteria, including natural antimicrobial peptides, have shown great therapeutic potential worldwide. Among these peptides, snake venom cathelicidins are being widely exploited, because the variation in the composition of the venom reflects a range of biological activities that may be of biotechnological interest. Cathelicidins are short, cationic, and amphipathic molecules. They play an important role in host defense against microbial infections. We are currently facing a strong limitation on pharmacological interventions for infection control, which has become increasingly complex due to the lack of effective therapeutic options. In this review, we will focus on natural snake venom cathelicidins as promising candidates for the development of new antibacterial agents to fight antibiotic-resistant bacteria. We will highlight their antibacterial and antibiofilm activities, mechanism of action, and modulation of the innate immune response.

Keywords: antimicrobial peptides; cathelicidins; host-defense peptides; natural peptides; snake venom.

Figure 1

Cathelicidins' mechanisms of action. (A), Cathelicidin structural modification by electrostatic interaction with Gram-negative bacterial membrane. (B), Bacterial membrane disruption caused by cathelicidins. (C), Inhibition of ATP synthesis/hydrolysis caused through cathelicidins binding to ATP synthase. Created with BioRender.com.

Figure 2

Immunomodulatory response of cathelicidins toward bacterial LPS mediated by TLR4-MD2 complex receptor signaling. Lipopolysaccharide (LPS), the main component of the outer membrane of Gram-negative bacteria, is recognized and activated by immune defense cells, and can bind to membrane receptors of variable specificity and induce the synthesis of inflammatory mediators. LPS is recognized by LBP (LPS-binding proteins) and the LPS-LBP complex binds to the CD14 receptor, a leukocyte membrane-expressed glycoprotein. In turn, LPS is presented to the TLR4-MD2 complex (Toll-like receptor 4 and myeloid differentiation factor 2), activating the transcription factors NF-κB (nuclear factor-κB) and IRF (interferon regulatory factors), consequently inducing the production of pro-inflammatory cytokines, chemokines, and nitric oxide (NO). The direct interaction of cathelicidin with bacterial LPS, the CD14 co-receptor or TLR4, allows modulation of the immune response, reducing its pro-inflammatory effects. Created with BioRender.com

Figure 3

Representation of the helix-Pro-coil structural profile that has been described for snake venom CRAMPs. (A), Sequence alignment highlighting a conserved proline residue at the C-terminus region of all snake venom CRAMPs here described. *Indicates conserved residues between all sequences. (B), Lowest free energy structure obtained by solution NMR for crotalicidin (PDB entry: 2mwt) (Falcao et al., 2015). Although the two lysine residues that precede the proline appear unstructured, they are structurally stable among the 20 lowest free energy structures deposited for crotalicidin. In contrast, the residues after the proline are highly flexible. The proline residue is represented as yellow sticks.