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.

Introduction: Bacterial resistance is a worldwide public health problem, requiring new therapeutic options. An alternative approach to this problem is the use of animal toxins isolated from snake venom, such as phospholipases A2 (PLA2), which have important antimicrobial activities. Bothropserythromelas is one of the snake species in the northeast of Brazil that attracts great medical-scientific interest. Here, we aimed to purify and characterize a PLA2 from B. erythromelas, searching for heterologous activities against bacterial biofilms. Methods: Venom extraction and quantification were followed by reverse-phase high-performance liquid chromatography (RP-HPLC) in C18 column, matrix-assisted ionization time-of-flight (MALDI-ToF) mass spectrometry, and sequencing by Edman degradation. All experiments were monitored by specific activity using a 4-nitro-3-(octanoyloxy) benzoic acid (4N3OBA) substrate. In addition, hemolytic tests and antibacterial tests including action against Escherichiacoli, Staphylococcusaureus, and Acinetobacterbaumannii were carried out. Moreover, tests of antibiofilm action against A. baumannii were also performed. Results: PLA2, after one purification step, presented 31 N-terminal amino acid residues and a molecular weight of 13.6564 Da, with enzymatic activity confirmed in 0.06 µM concentration. Antibacterial activity against S. aureus (IC50 = 30.2 µM) and antibiofilm activity against A. baumannii (IC50 = 1.1 µM) were observed. Conclusions: This is the first time that PLA2 purified from B. erythromelas venom has appeared as an alternative candidate in studies of new antibacterial medicines.

Several antimicrobial peptides (AMPs) have been reported in amphibian toxins, as temporin‐PTa from Hylarana picturata. The amino acid distribution within a helical structure of AMPs favors the design of new bioactive peptides. Therefore, this work reports the rational design of two new synthetic peptides denominated Hp‐MAP1 and Hp‐MAP2 derived from temporin‐PTa. These peptides present an amphipathic helix with positive charges of +4 and +5, hydrophobic moment (<µH>) of 0.66 and 0.72 and hydrophobicity () of 0.49 and 0.41, respectively. Hp‐MAP1 and Hp‐MAP2 displayed in vitro activity against Gram‐negative and Gram‐positive bacteria from 2.8 to 92 µM, without presenting hemolytic effects. Molecular dynamics simulation suggested that the parent and designed temporin‐like peptides lack structural stability in an aqueous solution. By contrast, α‐helical structures were predicted in hydrophobic and anionic environments. Additionally, the peptides were simulated on mimetic membranes composed of anionic and neutral phospholipids 1,2‐dipalmitoylsn‐glycerol‐3‐phosphatidylglycerol (DPPG‐anionic), 1,2‐dipalmitoyl‐sn‐lyco‐3 phosphatidylethanolamine (DPPE‐neutral). When in contact with DPPG/DPPE (90:10) and DPPG/DPPE (50:50) temporin‐PTa, Hp‐MAP1 and Hp‐MAP2 established interactions guided by hydrogen and saline bounds. Therefore, the findings described here reveal that the optimization of the amphipathic α‐helical cationic peptides Hp‐MAP1 and Hp‐MAP2 enabled the generation of new synthetic antimicrobial agents to combat pathogenic microorganisms.