Antibacterial properties of snake venom components
- 632 Downloads
An increasing problem in the field of health protection is the emergence of drug-resistant and multi-drug-resistant bacterial strains. They cause a number of infections, including hospital infections, which currently available antibiotics are unable to fight. Therefore, many studies are devoted to the search for new therapeutic agents with bactericidal and bacteriostatic properties. One of the latest concepts is to search for this type of substances among toxins produced by venomous animals. In this approach, however, special attention is paid to snake venom because it contains molecules with antibacterial properties. Thorough investigations have shown that the phospholipases A2 (PLA2) and l-amino acids oxidases (LAAO), as well as fragments of these enzymes, are mainly responsible for the bactericidal properties of snake venoms. Some preliminary research studies also suggest that fragments of three-finger toxins (3FTx) are bactericidal. It has also been proven that some snakes produce antibacterial peptides (AMP) homologous to human defensins and cathelicidins. The presence of these proteins and peptides means that snake venoms continue to be an interesting material for researchers and can be perceived as a promising source of antibacterial agents.
KeywordsSnake venom Phospholipases A2 l-Amino acid oxidases Antimicrobial properties
The most important clinical problem in the field of microbiology today is growing resistance to antibiotics in bacteria. According to the WHO, bacterial infections involving multi-drug-resistant (MDR) strains are one of the ten leading causes of death worldwide (Lopez et al. 2006). Moreover, antimicrobial resistance is considered to be one of the greatest threats to human health globally (Walker et al. 2009). Unfortunately, new examples of bacteria with antibiotic resistance appear every year. It is estimated that more than 90% of Staphylococcus aureus strains are resistant to β-lactam antibiotics (Panlilio 1992). Such resistance is shown, for example, by already long-known strains like methicillin-resistant S. aureus (MRSA) and penicillin-resistant Streptococcus pneumoniae (PRSP) (Al Ahmadi et al. 2010). Recent studies have also shown that excessive use of antibiotics, such as vancomycin, may lead to developing vancomycin-intermediate (VISA)/vancomycin-resistant (VRSA) strains, like, for example, in the case of enterococci (Appelbaum 2006; Cázares-Domínguez et al. 2015). Other bacteria such as Pseudomonas, Klebsiella, Enterobacter, Acinetobacter, Salmonella or Enterococcus have also developed several ways to resist antibiotics (Al Ahmadi et al. 2010). It is estimated that 23,000 and 25,000 people die every year in the USA and Europe, respectively, from infections caused by multidrug-resistant bacteria (CDC 2013; Blair et al. 2015). Presently existing and still appearing multiple-resistant strains increase the risk of bacterial infections, which become more and more threatening, as currently, we lack proper tools and drugs to combat them. Recently, many antimicrobials are at various stages of development and phases of clinical trials. However, it is still very clear that the discovery of new, potent antibacterial agents capable of overcoming drug resistance as well as the development of antibacterials with a new mechanism of action remains of the highest priority (Guardabassi and Kruse 2003; Ang et al. 2004; Roos 2004; de Lima et al. 2005; Al Ahmadi et al. 2010; Perumal Samy et al. 2017).
The pharmacological potential of snake venom
The composition of snake venom depends mainly on the species, but also on age, sex or type of food consumed (Koh et al. 2006). However, it should be mentioned that some systematic groups do not contain venomous snakes, e.g., boa or pythons. In some other groups, however, all the species classified there are venomous. Venomous snakes belong to following families: Viperidae (viperids, including vipers and rattlesnakes), Elapidae (elapids, including cobras, mambas and taipans), Hydrophiidae (sea snakes) and Colubridae (colubrids, although only some of them are venomous) (Gold et al. 2002; Warrell 2010; Burbrink and Crother 2011; Warrell 2019).
Snake venoms are complex mixtures of several families of protein-origin components that can be divided into 4 groups. The dominant are three-finger toxins (3FTx), phospholipases A2 (PLA2), snake venom metalloproteases (SVMP) and snake venom serine proteases (SVSP). The second group includes proteins commonly present in the venom, but in much smaller amounts: Kunitz peptides (KUN), Cysteine-Rich Secretory Proteins (CRiSP), l-amino acid oxidases (LAAO), C-type lectins (CTL), disintegrins (DIS), natriuretic peptides (NP). The third group contains proteins that are less commonly observed in venoms such as venom nerve growth factor (VNGF), vascular endothelial growth factor (VEGF), acetylcholinesterases, hyaluronidases, 5′-nucleotidases, phosphodiesterases (PDE), snake venom metalloprotease inhibitors and others. The last group contains rare proteins, among others: cobra venom factors (CVF), galactose-binding proteins, aminopeptidases or waprins. Of course, not all protein groups are found in all venomous snakes. For example, for elapids in general the most abundant proteins are phospholipases A2 and 3FTx, however, this is not true for example for mambas. Their venom consists mostly of Kunitz peptides. On the other hand for viperids in general the most abundant groups are PLA2s and proteases with different proportions of serine proteases and metalloproteases in different systematic groups (Tasoulis and Isbister 2017).
Snake venoms in drug design and development
Snake venoms are known to be a complicated mixture of proteins and peptides with great potential for drug design and development, which can ultimately lead to their clinical use. Unfortunately, the therapeutic use of peptide-origin drugs is problematic, especially due to their low bioavailability through the oral route, poor permeability, metabolic inactivation, the danger of proteolysis or enzymatic degradation, binding to plasma protein and finally, toxicity (Craik et al. 2013). Presently these limitations are being overcome through various approaches, for example, using antimicrobial peptides (AMP) externally in contact lenses coating (Dutta et al. 2014), using biocompatible carriers which enhance bioavailability (Lax and Meenan 2012; Maia et al. 2014) or encapsulation in biodegradable polymers (Anthony and Freda 2009). Snake venom toxins, from small peptides to large proteins, are very interesting, pharmacologically active compounds with wide chemical and functional variability, stability and specificity. They may inspire innovative discoveries including development of research tools or invention of new drugs like antibacterial and antitumor compounds. Currently, it is believed that pharmaceutical and biomedical research should lead to routine use of venom toxins as structural templates for the design and synthesis of novel and efficient therapeutic agents (de Oliveira-Junior et al. 2013; Almeida et al. 2017, 2018).
Currently, hundreds of therapeutic peptides are under development and at different stages of clinical tests (Kaspar and Reichert 2013; Uhlig et al. 2014). Majority of them are involved in cancer: e.g., disintegrins with antiangiogenesis effect or LAAOs inducing apoptosis (Li et al. 2018b) and cardiovascular diseases treatment, besides the examples mentioned in the previous paragraph, also, e.g., natriuretic peptides and ion channel blockers (Koh and Kini 2012). However, there are also peptides tested for pain treatment (e.g., mambalgin from Dendroaspis polylepis venom) (Diochot et al. 2012) and infectious diseases, for example LAAOs from Trimeresurus stejnegeri venom inhibit infection and replication of HIV-1 virus (Zhang et al. 2003) and LAAOs from Bothrops jararaca have antiviral (Dengue virus) and antiprotozoal (trypanocidal and leishmanicide) activities (Sant’Ana et al. 2008).
The use of venom components for drug discovery is rapidly increasing, though it is still mostly an unrealized prospect due to recurrent technical bottlenecks that represent venom exploration (Lewis and Garcia 2003). It is estimated that although all animal venoms consist of over 40 million proteins and peptides, only a very small fraction of them are known (Escoubas and King 2009). The advent and development of -omic techniques has led to discovery of an increasing number of toxins with known sequences and structures, which are available for biomedical and biotechnological exploitation (King 2011). The future direction of venom research with the use of modern ‘omics’ techniques such as genomics, transcriptomics and proteomics should lead to identification and characterization of new therapeutic molecules from animal venoms. According to the authorities in this field, the key for the search of novel antimicrobial molecules is the characterization of previously unexplored and rare animal venoms, as they may be the new source of antibacterial molecules (Perumal Samy et al. 2017).
The antibiotic potential of snake venom
Antimicrobial agents are used in medicine to treat infections caused by microbes from different classes of pathogenic organisms, namely viruses, protozoa, fungi and bacteria, including among others, rickettsia, mycoplasma and chlamydia. Among them, bacteria are the largest and most diverse group of pathogenic microorganisms (Rouault 2004). Antimicrobial agents normally used to treat bacterial infections are divided into two groups: bacteriostatics and bactericidals. Bacteriostatic agents arrest the growth of bacteria (e.g., sulphonamides, tetracycline, chloramphenicol), bactericidal agents, on the other hand, kill bacterial cells through disruption of cell wall/membrane function (Chao et al. 2013). The effectiveness of both, existing drugs and venom components, depend on the type of bacteria. For example, the bactericidal activity of Bothrops alternatus venom is higher against Escherichia coli and S. aureus versus Pseudomonas aeruginosa and Enterococcus faecalis (Bustillo et al. 2008).
Recent studies prove that many venoms and venom components produced by different venomous animals show potential antibacterial activity. These include snake (Perumal Samy et al. 2007; Al Ahmadi et al. 2010; Ferreira et al. 2011; Perumal Samy et al. 2014b), spider (Haeberli et al. 2000; Budnik et al. 2004; Kozlov et al. 2006; Benli and Yigit 2008), scorpion (Conde et al. 2000; Torres-Larios et al. 2002), honeybee (EL-Feel et al. 2015; Leandro et al. 2015) and wasp venoms (Jalaei et al. 2014).
Summary of previously tested venoms for antibacterial properties
Accary et al. (2014)
Al Ahmadi et al. (2010)
Al-Asmari et al. (2015)
Al-Asmari et al. (2015)
Bustillo et al. (2008)
Ferreira et al. (2011)
Ferreira et al. (2011)
Iğci et al. (2016)
Jaoudeh et al. (2017)
Moridikia et al. (2018)
Daboia russelii russelii
Perumal Samy et al. (2006)
Daboia russelii russelii
Naja naja naja
Perumal Samy et al. (2007)
Rangsipanuratn et al. (2019)
Sachidananda et al. (2007)
San et al. (2010)
Naja naja naja
Shebl et al. (2012)
Naja naja naja
Shebl et al. (2012)
Naja naja naja
Shebl et al. (2012)
Naja naja naja
Shebl et al. (2012)
Yalcın et al. (2013)
Snake venom components with antimicrobial properties
Generally, components of snake venoms can be divided into peptide-origin and non-peptide-origin. The first group is discussed in the second paragraph of the article and it may constitute more than 90% of venom’s dry weight, while the second group consists of low molecular weight organic compounds such as carbohydrates, serotonin, histamine, citrate, and nucleosides; and inorganic ions such as calcium, cobalt, magnesium, copper, iron, and potassium. The toxic effect of venom, both in the context of victim bite and potential antibacterial effect, is caused by the components of the first group (Izidoro et al. 2014).
One of the most common groups of enzymes present in both elapid and viperid venoms are phospholipases A2, which can be divided into basic and acidic PLA2s. Basic PLA2s are usually responsible for major toxic effects induced by snake venoms, while acidic PLA2s tend to have a lower toxicity (Doley et al. 2010). The svPLA2s (snake venom PLA2s) are very interesting enzymes due to their potential for being therapeutic lead molecules with antimicrobial properties against enveloped bacteria, viruses, fungi, parasites, and protozoa (Perumal Samy et al. 2007, 2012). Basic PLA2 from Crotalus durissus terrificus has strong bactericidal effects against both Gram-positive and -negative bacteria (Toyama et al. 2003). An acidic PLA2 from Porthidium nasutum venom has bactericidal activity against S. aureus with MIC (minimal inhibitory concentration) value of 32 µg/ml (Vargas et al. 2012). A myotoxic PLA2 (MjTX-II) from B. moojeni demonstrates antimicrobial activity against E. coli (Okubo et al. 2012). Phospholipase A2 from Crotalus adamanteus, called toxin-II (CaTx-II) has antibacterial properties against S. aureus and Burkholderia pseudomallei and also inhibits Enterobacter aerogenes growth causing disintegration of cell wall, by the generation of pores in membrane. Moreover, it has been shown that this protein can promote wound healing (Perumal Samy et al. 2014b). Membrane permeabilization is also caused by basic myotoxin crotamine from C. durissus terrificus and, what is interesting, this effect is limited to prokaryotic cells because it acts without any haemolytic effects (Oguiura et al. 2011). New PLA2 from Walterinnesia aegyptia venom has antimicrobial properties against several human pathogenic strains (Ben Bacha et al. 2018) and PLA2 from Pseudonaja textilis is able to inhibit the growth of S. aureus (Perumal Samy et al. 2007) and Burkholderia pseudomallei (Perumal Samy et al. 2006). The mechanism of action in this case is associated with pore formation and membrane damaging effects on the bacterial cell wall without any cytotoxic effects on lung and skin fibroblast cells (Perumal Samy et al. 2014b).
What is also interesting, peptides formed from a svPLA2 fragmentation are also able to interact with lipopolysaccharide (LPS), particularly the lipid A component of S. aureus, causing membrane permeabilization, and exerting bactericidal effects (Perumal Samy et al. 2014b). Cysteine-rich AMPs in particular may have a broad spectrum of antimicrobial properties. They are characterized by flexibility of structure and positive charge, which are essential for the enrichment of antibacterial activity caused by hydrophobic attraction to bacterial membrane with negatively charged components (Perumal Samy et al. 2017). Different cationic peptides derived from svPLA2s from Bothrops asper present antimicrobial activity against Klebsiella pneumoniae, fight peritonitis induced by Salmonella enterica in mice and cause membrane permeabilization of S. aureus (Santamaria et al. 2005). But what is most important, these peptides, which are composed of 10- to 22-odd amino acids, derived from the carboxy terminus of the svPLA2s, are less toxic for eukaryotic cells and more bactericidal than the parent molecules. That is why this type of natural peptides and others may become a base for novel drugs design and lead to the production of new drugs with potential therapeutic value in the near future (White 2000; Koh et al. 2006).
l-Amino acid oxidases
The second major group of venom enzymes responsible for antimicrobial properties is l-amino acid oxidases (LAAO). They are usually homodimeric proteins with covalently linked cofactors (FAD or FMN), however, their structures, molecular masses, and isoelectric points can be significantly different. Concentration of snake venom LAAOs varies between systematic groups and affects venom toxicity and its color. Those enzymes catalyze the oxidative deamination of hydrophobic and aromatic amino acids in a wide range of pHs and temperatures. In the first step of the reaction the amino acid substrate is oxidized to an imino acid, with a simultaneous reduction of the cofactor. In the second step the imino acid undergoes nonenzymatic hydrolysis, yielding α-keto acid and ammonia. In order for the next reaction to occur, it is necessary to close the catalytic cycle by regenerating the cofactor. Reoxidizing of cofactor takes place in the presence of molecular oxygen and thus generates hydrogen peroxide. It is believed that the production of hydrogen peroxide opens perspectives for new applications of these enzymes as bactericidal, antiviral, and antitumor agents, making them a promising biotechnological agent. In prey’s body they induce changes in platelet function, which cause local effects on plasma clotting disorders among other things. But in vitro, LAAOs also trigger apoptosis in various cell lines and show antimicrobial and antiparasitic activity (Izidoro et al. 2014).
Bactericidal effect of snake venom l-amino acid oxidases was reported in the case of several species of both viperids (e.g., Ciscotto et al. 2009; Costa Torres et al. 2010; Vargas et al. 2013) and elapids (e.g., Samel et al. 2008; Lee et al. 2011). Generally, snake venom LAAOs exhibit various levels of antibacterial activity against different bacteria strains. l-Amino acid oxidase from P. australis venom is 17.5 times more effective than tetracycline against Aeromonas hydrophila on a molar basis (Stiles et al. 1999). The venom of Bothrops leucurus inhibits S. aureus growth in a dose-dependent manner, with a MIC of 25 µg/ml. LAAOs from C. adamanteus and B. asper exert antibacterial activity against S. aureus and Proteus mirabilis same as svLAAO from Bothrops venoms (Tempone et al. 2001; Izidoro et al. 2006; Costa Torres et al. 2010). Another LAAO from Bothrops pirajai controls the growth of Pseudomonas aeruginosa and Escherichia coli (Izidoro et al. 2006). And as in the case of PLA2s, also small fragments of LAAO show enhanced antimicrobial activity. These small peptides could be promising candidates in the new antibiotics design (Okubo et al. 2012).
There are at least two hypotheses about antibacterial activity of LAAOs. The first is related to the oxidized form of the cofactor of the enzyme (FAD or FMN). This cofactor interacts with l-amino acids which can then act on nucleic acids, proteins, and the plasma membrane (Izidoro et al. 2014). The second involves hydrogen peroxide which, after interaction with the bacterial membrane, can provoke lipoperoxidation (Toyama et al. 2006), DNA fragmentation (Braga et al. 2008), and in consequence cell death. It is also probable that LAAO can directly oxidize amino acids in proteins (Ande et al. 2008). Generally it is believed that the most probable mechanism of bactericidal activity of LAAOs involves oxidative stress in the bacteria cell, triggering disorganization and permeabilization of the plasma membrane and finally death of the cell, all caused by presence of hydrogen peroxide in the reaction medium (Izidoro et al. 2014).
Staphylococcus aureus and the coagulase-negative S. epidermidis, colonizing the nose and skin, are the most common commensal bacteria causing infections in humans and other mammals. The infection develops only when the protective layer of the human epithelium is breached and mechanisms of host immunity fail. These mechanisms include antimicrobial peptides (AMP) present on the skin and in the sweat. They are the first line of innate immune defenses on the human skin and also form part of the mechanisms by which bacteria are eliminated in the neutrophil phagosome after phagocytosis. AMPs in humans belong to two major groups: defensins and cathelicidins and many of them are active against staphylococci (Joo and Otto 2015).
Similarly to humans, other animals including snakes, produce small cationic antimicrobial peptides (cAMP) called cathelicidins. These peptides have a broad-spectrum of antimicrobial activity against a wide variety of bacteria, enveloped viruses, and fungi (Perumal Samy et al. 2017). Transcriptomic analyses of venom glands of several species (Naja atra, Bungarus fasciatus and Ophiophagus hannah) reveal that snakes’ cathelicidins are highly homologous with AMPs found in lysosomes of cells in the immune system and have strong antibacterial properties (Wang et al. 2008, 2011; Zhao et al. 2008). BF-30, cathelicidin-type peptide derived from B. fasciatus is very effective against diverse antibiotic-resistant bacteria, including those that cause wounds (MRSA) (Chen et al. 2011a). It was shown that it reduces number of bacteria at the wound, but also prevents inflammation and accelerates wound healing (Zhou et al. 2011; Du et al. 2015). Cathelicidin (OH-CATH) from Ophiophagus hannah and its analogs exert strong antibacterial and weak hemolytic activity. They are very effective against Acinetobacter spp., including multi-drug-resistant Acinetobacter baumannii (MRAB) and methicillin-resistant Staphylococcus aureus (MRSA) and their effectiveness is higher than that of the 9 routinely used antibiotics (Zhao et al. 2018). The myotoxin from Crotalus durissus venom called crotamine is on the other hand structurally related to beta-defensin antimicrobial peptides (AMP) found in vertebrate animals (Oguiura et al. 2011). Whole crotamine-myotoxin family shows high degree of homology (60–80%) with beta-defensin (Mancin et al. 1998; Nicastro et al. 2003) which makes them a very interesting subject for future research.
Another example of an interesting protein is omwaprin originating from Oxyuranus microlepidotus venom. It is an acidic protein belonging to the waprin family (whey acidic proteins) and it has selective antibacterial properties against Gram-positive bacteria. Its action is based on damaging of the cell membrane of bacteria, which in consequence leads to the leakage of cell contents and cell death. Interestingly, this protein does not damage human cells, which has been proven in tests on erythrocytes (Nair et al. 2007).
Similar to 3FTxs and waprins, C-type lectin-like proteins are an example of venom components without enzymatic activity. Representatives of this group often show contradictory actions: some induce platelet aggregation and agglutination, while others inhibit this effect. Both purified lectins, such as the one from Bothrops leucurus venom, namely BlL, and lectin homologs, have antimicrobial properties. Mentioned BlL protein from B. leucurus is effective against Staphylococcus aureus, Enterococcus faecalis and Bacillus subtilis (Nunes Edos et al. 2011) and the protein from Bothrops jararacussu acts against Staphylococcus aureus (Klein et al. 2015) whereas homologs of convulxin from Crotalus durissus terrificus decrease the growth of Xanthomonas axonopodis and Clavibacter michiganensis michiganensis (Rádis-Baptista et al. 2006).
A final example of a venom component with antibacterial properties is enzyme AHM from Agkistrodon halys belonging to metalloproteinase family. This protein is very effective against Proteus vulgaris, Proteus mirabilis, Staphylococcus aureus and multi-drug resistant Burkholderia pseudomallei. The mechanism of action is associated with damage to the membranes, wrinkling of cell surfaces, leakage of cell contents and formation of vesicles on cell surfaces, with the consequence that the membrane and wall lose their integrity (Perumal Samy et al. 2008).
In the era of great threat posed by antibiotic-resistant strains of bacteria, we face a great challenge which is to develop modern methods of antibacterial therapies. One of the promising trends is the search for compounds with antibacterial potential among venom components. It has been repeatedly proven that both whole snake venom and its individual components, or even their fragments, have the desired properties and are therefore a potential source of new antibiotics. This approach is all the more promising as there are known examples of the development of effective drugs based on proteins and peptides derived from snake venom.
Moreover, much attention should be devoted to understanding the different mechanisms responsible for the antibacterial activity of venom-based drugs. This will certainly enable finding new promising drug templates as well as optimizing existing structures. Therefore, the identification of new venom-origin agents, combined with alternative routes of administration, developed in recent years, make them a very promising line of research with great potential for the future. With increased approval of peptide-based drugs and advances in peptide-associated technologies, they are becoming more and more medically significant.
Compliance with ethical standards
Conflict of interest
The authors declare no conflict of interest.
- Almeida JR, Resende LM, Watanabe RK, Corassola VC, Huancahuire-Vega S, Caldeira CAdS, Coutinho-Neto A, Soares AM, Vale N, Gomes PADC, Marangoni S, Calderon LdA, Silva SLD (2017) Snake venom peptides and low mass proteins: molecular tools and therapeutic agents. Curr Med Chem 24:3254–3282. https://doi.org/10.2174/0929867323666161028155611 CrossRefPubMedGoogle Scholar
- Almeida JR, Mendes B, Lancellotti M, Marangoni S, Vale N, Passos Ó, Ramos MJ, Fernandes PA, Gomes P, Da Silva SL (2018) A novel synthetic peptide inspired on Lys49 phospholipase A2 from Crotalus oreganus abyssus snake venom active against multidrug-resistant clinical isolates. Eur J Med Chem 149:248–256. https://doi.org/10.1016/j.ejmech.2018.02.05 CrossRefPubMedGoogle Scholar
- Braga MDM, Martins AMC, Amora DN, de Menezes DB, Toyama MH, Toyama DO, Marangoni S, Alves CD, Barbosa PS, de Sousa Alves R, Fonteles MC, Monteiro HS (2008) Purification and biological effects of l-amino acid oxidase isolated from Bothrops insularis venom. Toxicon 51(2):199–207. https://doi.org/10.1016/j.toxicon.2007.09.003 CrossRefPubMedGoogle Scholar
- Budnik BA, Olsen JV, Egorov TV, Anisimova VE, Galkina TG, Musolyamov AK, Grishin EV, Zubarev RA (2004) De novo sequencing of antimicrobial peptides isolated from the venom glands of the wolf spider Lycosas ingoriensis. J Mass Spectrom 39:193–201. https://doi.org/10.1002/jms.577 CrossRefPubMedGoogle Scholar
- Bustillo S, Leiva LC, Merino L, Acosta O, de Kier Joffé EB, Gorodner JO (2008) Antimicrobial activity of Bothrops alternatus venom from the Northeast of Argentine. Rev Latinoam Microbiol 50(3):79–82Google Scholar
- Cázares-Domínguez V, Cruz-Córdova A, Ochoa SA, Escalona G, Arellano-Galindo J, Rodríguez-Leviz A, Hernández-Castro R, López-Villegas EO, Xicohtencatl-Cortes J (2015) Vancomycin tolerant, methicillin-resistant Staphylococcus aureus reveals the effects of vancomycin on cell wall thickening. PLoS ONE 10:e0118791. https://doi.org/10.1371/journal.pone.0118791 CrossRefPubMedPubMedCentralGoogle Scholar
- CDC Centers for Disease Control and Prevention (2013) Antibiotic resistance threats in the United States. http://www.cdc.gov/drugresistance/threat-report-2013/. Accessed 08 July 2019
- Chao MC, Kieser KJ, Minami S, Mavrici D, Aldridge BB, Fortune SM, Alber T, Rubin EJ (2013) Protein complexes and proteolytic activation of the cell wall hydrolase RipA regulate septal resolution in mycobacteria. PLoS Pathog 9(2):e1003197. https://doi.org/10.1371/journal.ppat.1003197 CrossRefPubMedPubMedCentralGoogle Scholar
- Ciscotto P, Machado de Avila RA, Coelho EA, Oliveira J, Diniz CG, Farías LM, de Carvalho MA, Maria WS, Sanchez EF, Borges A, Chávez-Olórtegui C (2009) Antigenic, microbicidal and antiparasitic properties of an l-amino acid oxidase isolated from Bothrops jararaca snake venom. Toxicon 53(3):330–341. https://doi.org/10.1016/j.toxicon.2008.12.004 CrossRefPubMedGoogle Scholar
- Costa Torres AF, Dantas RT, Toyama MH, DizFilho E, Zara FJ, Rodrigues de Queiroz MG, Pinto Nogueira NA, Rosa de Oliveira M, de Oliveira Toyama D, Monteiro HS, Martins AM (2010) Antibacterial and antiparasitic effects of Bothrops marajoensis venom and its fractions: phospholipase A2 and l-amino acid oxidase. Toxicon 55(4):795–804. https://doi.org/10.1016/j.toxicon.2009.11.013 CrossRefPubMedGoogle Scholar
- Costa TR, Menaldo DL, Oliveira CZ, Santos-Filho NA, Teixeira SS, Nomizo A, Fuly AL, Monteiro MC, de Souza BM, Palma MS, Stabeli RG, Sampaio SV, Soares AM (2008) Myotoxic phospholipases A2 isolated from Bothrops brazili snake venom and synthetic peptides derived from their C-terminal region: cytotoxic effect on microorganism and tumor cells. Peptides 29:1645–1656. https://doi.org/10.1016/j.peptides.2008.05.021 CrossRefPubMedGoogle Scholar
- Danilucci TM, Santos PK, Pachane BC, Pisani GFD, Lino RLB, Casali BC, Altei WF, Selistre-de-Araujo HS (2019) Recombinant RGD-disintegrin DisBa-01 blocks integrin αvβ3 and impairs VEGF signaling in endothelial cells. Cell Commun Signal 17(1):27. https://doi.org/10.1186/s12964-019-0339-1 CrossRefPubMedPubMedCentralGoogle Scholar
- Díaz C, Gutiérrez J, Lomonte B, Gené J (1991) The effect of myotoxins isolated from Bothrops snake venoms on multilamellar liposomes: relationship to phospholipase A 2, anticoagulant and myotoxic activities. Biochim Biophys Acta 1070:455–460. https://doi.org/10.1016/0005-2736(91)90086-n CrossRefPubMedGoogle Scholar
- Díaz C, León G, Rucavado A, Rojas N, Schroit J, Gutiérrez JM (2001) Modulation of the susceptibility of human erythrocytes to snake venom myotoxic phospholipases A2: role of negatively charged phospholipids as potential membrane binding sites. Arch Biochem Biophys 391:56–64. https://doi.org/10.1006/abbi.2001.2386 CrossRefPubMedGoogle Scholar
- Diniz-Sousa R, Caldeira CAS, Kayano AM, Paloschi MV, Pimenta DC, Simões-Silva R, Ferreira AS, Zanchi FB, Matos NB, Grabner FP, Calderon LA, Zuliani JP, Soares AM (2018) Identification of the molecular determinants of the antibacterial activity of LmutTX, a Lys49 phospholipase A2 homologue isolated from Lachesis muta muta Snake venom (Linnaeus, 1766). Basic Clin Pharmacol Toxicol 22(4):413–423. https://doi.org/10.1111/bcpt.12921 CrossRefGoogle Scholar
- Doley R, Zhou X, Kini RM (2010) Snake venom phospholipase A 2 enzymes. In: Mackessy SP (ed) Handbook of venoms and toxins of reptiles. CRC Press, Taylor & Francis Group, Boca Raton, pp 173–206Google Scholar
- El-Feel MA, Abdel-Rahman EH, Abed Al-Fattah MA (2015) Antibacterial activity of bee venom collected from Apis mellifera carniolan pure and hybrid races by two collection methods. Int J Curr Microbiol App Sci 4:141–149Google Scholar
- Ferreira BL, Santos OD, dos Santos AL, Rodrigues CR, de Freitas CC, Cabral LM, Castro HC (2011) Comparative analysis of Viperidae venoms antibacterial profile: a short communication for proteomics. Evid Based Complement Alternat Med 2011:960267. https://doi.org/10.1093/ecam/nen052 CrossRefPubMedPubMedCentralGoogle Scholar
- Izidoro LFM, Ribeiro MC, Souza GRL, Sant’Anna CD, Hamaguchi A, Homsi-Brandeburgo MI, Goulart LR, Beleboni RO, Nomizo A, Sampaio SV, Soares AM, Rodrigues VM (2006) Biochemical and functional characterization of an l-amino acid oxidase isolated from Bothrops pirajai snake venom. Bioorg Med Chem 14(20):7034–7043. https://doi.org/10.1016/j.bmc.2006.06.025 CrossRefPubMedGoogle Scholar
- Izidoro LF, Sobrinho JC, Mendes MM, Costa TR, Grabner AN, Rodrigues VM, da Silva SL, Zanchi FB, Zuliani JP, Fernandes CF, Calderon LA, Stábeli RG, Soares AM (2014) Snake venom l-amino acid oxidases: trends in pharmacology and biochemistry. Biomed Res Int 2014:196754. https://doi.org/10.1155/2014/196754 CrossRefPubMedPubMedCentralGoogle Scholar
- Jaoudeh CA, Hraoui-Bloquet S, Sadek R, Rizk R, Hleihel W (2017) Antibacterial effect of the Montivipera bornmuelleri crude venom against Salmonella enteritidis and Staphylococcus aureus. RJPBCS 8(2):137Google Scholar
- Kozlov SA, Vassilevski AV, Feofanov AY, Surovoy DV, Karpunin EV, Grishin E (2006) Latarcins antimicrobial and cytolytic peptides from venom of the spider Lachesana tarabaevi (Zodariidae) that exemplify biomolecular diversity. J Biol Chem 281(30):20983–20992. https://doi.org/10.1074/jbc.M602168200 CrossRefPubMedGoogle Scholar
- Lax R, Meenan C (2012) Challenges for therapeutic peptides part 1: on the inside, looking out. Innov Pharm Technol 42:54–56Google Scholar
- Leandro LF, Mendes CA, Casemiro LA, Vinholis AH, Cunha WR, de Almeida R, Martins CH (2015) Antimicrobial activity of apitoxin, melittin and phospholipases A 2 of honey bee (Apis mellifera) venom against oral pathogens. An Acad Bras Cienc 87:147–155. https://doi.org/10.1590/0001-3765201520130511 CrossRefPubMedGoogle Scholar
- Mancin AC, Soares AM, Andriao-Escarso SH, Faca VM, Green LJ, Zuccolotto S, Pela IR, Giglio JR (1998) The analgesic activity of crotamine, a neurotoxin from Crotalus durissus terrificus (South American rattlesnake) venom: a biochemical and pharmacological study. Toxicon 36:1927–1937. https://doi.org/10.1016/S0041-0101(98)00117-2 CrossRefPubMedGoogle Scholar
- Nunes Edos S, de Souza MA, Vaz AF, Santana GM, Gomes FS, Coelho LC, Paiva PM, da Silva RM, Silva-Lucca RA, Oliva ML, Guarnieri MC, Correia MT (2011) Purification of a lectin with antibacterial activity from Bothrops leucurus snake venom. Comp Biochem Physiol B Biochem Mol Biol 159(1):57–63. https://doi.org/10.1016/j.cbpb.2011.02.001 CrossRefPubMedGoogle Scholar
- Okubo BM, Silva ON, Migliolo L, Gomes DG, Porto WF, Batista CL, Ramos CS, Holanda HH, Dias SC, Franco OL, Moreno SE (2012) Evaluation of an antimicrobial l-amino acid oxidase and peptide derivates from Bothropoides mattogrosensis pitviper venom. PLoS ONE 7(3):e33639. https://doi.org/10.1371/journal.pone.0033639 CrossRefPubMedPubMedCentralGoogle Scholar
- Páramo L, Lomonte B, Pizarro-cerdá J, Bengoechea JA, Gorvel JP, Moreno E (1998) Bactericidal activity of Lys49 and Asp49 myotoxic phospholipases A 2 from Bothrops asper snake venom: synthetic Lys49 myotoxin II-(115-129)-peptide identifies its bactericidal region. Eur J Biochem 253:452–461. https://doi.org/10.1046/j.1432-1327.1998.2530452.x CrossRefPubMedGoogle Scholar
- Perumal Samy R, Pachiappan A, Gopalakrishnakone P, Thwin MM, Hian YE, Chow TKV, Bow H, Weng JT (2006) In vitro antibacterial activity of natural toxins and animal venoms tested against Burkholderia pseudomallei. BMC Infect Dis 6(100):1–16. https://doi.org/10.1186/1471-2334-6-100 CrossRefGoogle Scholar
- Perumal Samy R, Gopalakrishnakone P, Thwin MM, Chow TK, Bow H, Yap EH, Thong TW (2007) Antibacterial activity of snake, scorpion and bee venoms: a comparison with purified venom phospholipase A2 enzymes. J Appl Microbiol 102:650–659. https://doi.org/10.1111/j.1365-2672.2006.03161.x CrossRefPubMedGoogle Scholar
- Perumal Samy R, Manikandan J, Sethi G, Franco OL, Okonkwo JC, Stiles BG, Chow VTC, Gopalakrishnakone P, Qahtani MA (2014a) Snake venom proteins: development into antimicrobial and wound healing agents. Mini-Rev Org Chem 11:1–14. https://doi.org/10.2174/1570193X1101140402100131 CrossRefGoogle Scholar
- Perumal Samy R, Kandasamy M, Gopalakrishnakone P, Stiles BG, Rowan EG, Becker D, Shanmugam MK, Sethi G, Chow VT (2014b) Wound healing activity and mechanisms of action of an antibacterial protein from the venom of the eastern diamondback rattlesnake (Crotalus adamanteus). PLoS ONE 9:e80199. https://doi.org/10.1371/journal.pone.0080199 CrossRefGoogle Scholar
- Rádis-Baptista G, Moreno FB, de Lima Nogueira L, Martins AM, Toyama DO, Toyama MH, Cavada BS, Azevedo WF, Yamane T (2006) Crotacetin, a novel snake venom C-type lectin homolog of convulxin, exhibits an unpredictable antimicrobial activity. Cell Biochem Biophys 44:412–423. https://doi.org/10.1385/CBB:44:3:412 CrossRefPubMedGoogle Scholar
- Santamarıa C, Larios S, Quirós S, Pizarro-Cerda J, Gorvel J, Lomonte B, Moreno E (2005) Bactericidal and antiendotoxic properties of short cationic peptides derived from a snake venom Lys49 phospholipase A2. Antimicrob Agents Chemother 49:1340–1345. https://doi.org/10.1128/AAC.49.4.1340-1345.2005 CrossRefPubMedPubMedCentralGoogle Scholar
- Sant’Ana CD, Menaldo DL, Costa TR, Godoy H, Muller VD, Aquino VH, Albuquerque S, Sampaio SV, Monteiro MC, Stábeli RG, Soares AM (2008) Antiviral and antiparasite properties of an l-amino acid oxidase from the snake Bothrops jararaca: cloning and identification of a complete cDNA sequence. Biochem Pharmacol 76(2):279–288. https://doi.org/10.1016/j.bcp.2008.05.003 CrossRefPubMedGoogle Scholar
- Stábeli RG, Amui SF, Sant’Ana CD, Pires MG, Nomizo A, Monteiro MC, Romão PRT, Guerra-Sá R, Vieira CA, Giglio JR, Fontes MRM, Soares AM (2006) Bothrops moojeni myotoxin-II, a Lys49-phospholipase A2 homologue: an example of function versatility of snake venom proteins. Comp Biochem Physiol C 142:371–381. https://doi.org/10.1016/j.cbpc.2005.11.020 CrossRefGoogle Scholar
- Stiles BG, Sexton FW, Weinstein SA (1999) Antibacterial effects of different snake venoms: purification and characterization of antibacterial proteins from Pseudechis australis (Australian king brown or mulga snake) venom. Toxicon 29(9):1129–1141. https://doi.org/10.1016/0041-0101(91)90210-I CrossRefGoogle Scholar
- Toyama MH, Toyama DDO, Passero LFD, Laurenti MD, Corbett CE, Tomokane TY, Fonseca FV, Antunes E, Joazeiro PP, Beriam LO, Martins MA, Monteiro HS, Fonteles MC (2006) Isolation of a new l-amino acid oxidase from Crotalus durissus cascavella venom. Toxicon 47:47–57. https://doi.org/10.1016/j.toxicon.2005.09.008 CrossRefPubMedGoogle Scholar
- Walker B, Barrett S, Polasky S, Galaz V, Folke C, Engstrom G, Ackerman F, Arrow K, Carpenter S, Chopra K, Daily G, Ehrlich P, Hughes T, Kautsky N, Levin S, Maler K, Shogren J, Vincent J, Xepapadeas T, Zeeuw A (2009) Environment. Looming global-scale failures and missing institutions. Science 325:1345–1346. https://doi.org/10.1126/science.1175325 CrossRefPubMedGoogle Scholar
- Wang Y, Zhang Z, Chen L, Guang H, Li Z, Yang H, Li J, You D, Yu H, Lai R (2011) Cathelicidin-BF, a snake cathelicidin-derived antimicrobial peptide, could be an excellent therapeutic agent for Acne vulgaris. PLoS ONE 6:e22120. https://doi.org/10.1371/journal.pone.0022120 CrossRefPubMedPubMedCentralGoogle Scholar
- Zhao F, Lan XQ, Du Y, Chen PY, Zhao J, Zhao F, Lee WH, Zhang Y (2018) King cobra peptide OH-CATH30 as a potential candidate drug through clinic drug-resistant isolates. Zool Res 39(2):87–96. https://doi.org/10.24272/j.issn.2095-8137.2018.025 CrossRefPubMedPubMedCentralGoogle Scholar
Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.