Predicting antibacterial activity from snake venom proteomes

Autoři: Justin L. Rheubert aff001;  Michael F. Meyer aff002;  Raeshelle M. Strobel aff001;  Megan A. Pasternak aff001;  Robert A. Charvat aff001
Působiště autorů: Department of Biology, University of Findlay, Findlay, Ohio, United States of America aff001;  School of the Environment, Washington State University, Pullman, Washington, United States of America aff002
Vyšlo v časopise: PLoS ONE 15(1)
Kategorie: Research Article


The continued evolution of antibiotic resistance has increased the urgency for new antibiotic development, leading to exploration of non-traditional sources. In particular, snake venom has garnered attention for its potent antibacterial properties. Numerous studies describing snake venom proteomic composition as well as antibiotic efficacy have created an opportunity to synthesize relationships between venom proteomes and their antibacterial properties. Using literature reported values from peer-reviewed studies, our study generated models to predict efficacy given venom protein family composition, snake taxonomic family, bacterial Gram stain, bacterial morphology, and bacterial respiration strategy. We then applied our predictive models to untested snake species with known venom proteomic compositions. Overall, our results provide potential protein families that serve as accurate predictors of efficacy as well as promising organisms in terms of antibacterial properties of venom. The results from this study suggest potential future research trajectories for antibacterial properties in snake venom by offering hypotheses for a variety of taxa.

Klíčová slova:

Anaerobic bacteria – Antibacterials – Bacillus – Gram negative bacteria – Gram positive bacteria – Proteomes – Snakes – Venoms


1. Antão EM, Wagner-Ahlfs C. Antibiotikaresistenz: Eine gesellschaftliche Herausforderung. Bundesgesundheitsblatt—Gesundheitsforschung—Gesundheitsschutz. 2018;61: 499–506. doi: 10.1007/s00103-018-2726-y 29633036

2. Medina E, Pieper DH. Tackling threats and future problems of multidrug-resistant bacteria, in: Stadler M., Dersch P. (Eds.), How to Overcome the Antibiotic Crisis. Springer International Publishing, Cham, pp. 3–33. 2016.

3. Samy RP, Gopalakrishnakone P, Thwin MM, Chow TKV, Bow H, Yap EH, et al. Antibacterial activity of snake, scorpion and bee venoms: a comparison with purified venom phospholipase A2 enzymes. J Appl Microbiol. 2007;102: 650–659. doi: 10.1111/j.1365-2672.2006.03161.x 17309613

4. de Lima DC, Alvarez Abreu P, de Freitas CC, Santos DO, Borges RO, dos Santos TC, et al. Snake venom: any clue for antibiotics and CAM? Evid Based Complement Alternat Med. 2005;2: 39–47. doi: 10.1093/ecam/neh063 15841277

5. Mackessy SP, Saviola AJ. Understanding Biological Roles of Venoms Among the Caenophidia: The importance of rear-fanged snakes. Integr Comp Biol. 2016;56: 1004–1021. doi: 10.1093/icb/icw110 27639275

6. Phua CS, Vejayan J, Ambu S, Ponnudurai G, Gorajana A. Purification and antibacterial activities of an L-amino acid oxidase from king cobra (Ophiophagus hannah) venom. J Venom Anim Toxins Trop Dis. 2012;18: 198–207.

7. San T, Vejayan J, Shanmugam K, Ibrahim H. Screening antimicrobial activity of venoms from snake commonly found in Malaysia. J Appl Sci. 2010;10: 2328–2332.

8. Charvat RA, Strobel RM, Pasternak MA, Klass SM, Rheubert JL. Analysis of snake venom composition and antimicrobial activity. Toxicon. 2018;150: 151–167. doi: 10.1016/j.toxicon.2018.05.016 29800609

9. Stiles BG, Sexton FW, Weinstein SA. Antibacterial effects of different snake venoms: purification and characterization of antibacterial proteins from Pseudechis australis (Australian king brown or mulga snake) venom. Toxicon. 1991;29: 1129–1141. doi: 10.1016/0041-0101(91)90210-i 1796476

10. Calvete JJ, Fasoli E, Sanz L, Boschetti E, Righetti PG. Exploring the venom proteome of the western diamondback rattlesnake, Crotalus atrox, via snake venomics and combinatorial peptide ligand library approaches. J Proteome Res. 2009;8: 3055–3067. doi: 10.1021/pr900249q 19371136

11. Calvete JJ, Sanz L, Cid P, de la Torre P, Flores-Díaz M, Dos Santos MC, et al. Snake venomics of the Central American rattlesnake Crotalus simus and the South American Crotalus durissus complex points to neurotoxicity as an adaptive paedomorphic trend along Crotalus dispersal in South America. J Proteome Res. 2010;9: 528–544. doi: 10.1021/pr9008749 19863078

12. Samel M, Tõnismägi K, Rönnholm G, Vija H, Siigur J, Kalkkinen N, et al. L-Amino acid oxidase from Naja naja oxiana venom. Comp Biochem Physiol B Biochem Mol Biol. 2008;149: 572–580. doi: 10.1016/j.cbpb.2007.11.008 18294891

13. Xie JP, Yue J, Xiong YL, Wang WY, Yu SQ, Wang HH. In vitro activities of small peptides from snake venom against clinical isolates of drug-resistant Mycobacterium tuberculosis. Int J Antimicrob Agents. 2003;22: 172–174. doi: 10.1016/s0924-8579(03)00110-9 12927960

14. Sokal R, Rohlf F. Biometry: the principles and practice of statistics in biological research. 4th ed. W.H. Freeman: New York, NY. 2012., 4th ed. W.H. Freeman, New York, NY. 2012.

15. Korkmaz M, Güney S, Yiğîiter ŞY. The importance of logistic regression implementations in the Turkish livestock sector and logistic regression implementations/fields. J Agric Fac HRU. 2012;16: 25–36.

16. Winfree A. The Geometry of Biological Time. Springer-Verlag, New York, NY. 2001.

17. Akaike H. Information theory and an extension of the maximum likelihood principle. in Petrov BN, Csáki F., 2nd International Symposium on Information Theory, Tsahkadsor, Armenia, USSR, September 2–8, 1971, Budapest: Akadémiai Kiadó, pp. 267–281. 1973.

18. Burnham KP, Anderson DR, Burnham KP. Model selection and multimodel inference: a practical information-theoretic approach, 2nd ed. ed. Springer, New York. 2002.

19. McFadden D. Conditional logit analysis of qualitative choice behavior. pp. 105–142 in Zarembka P. (ed.), Frontiers in Econometrics. Academic Press. 1974.

20. Mason SJ, Graham NE. Areas beneath the relative operating characteristics (ROC) and relative operating levels (ROL) curves: Statistical significance and interpretation. Q J R Meteorol Soc. 2002;128: 2145–2166.

21. Katz SL, Izmest’eva LR, Hampton SE, Ozersky T, Shchapov K, Moore MV, et al. The “Melosira years” of Lake Baikal: Winter environmental conditions at ice onset predict under-ice algal blooms in spring: Resolving Melosira years on Lake Baikal. Limnol Oceanogr. 2015;60: 1950–1964.

22. Johnson RA, Wichern DV. Applied Multivariate Statistical Analysis, 6th ed. Prentice Hall, Upper Saddle River, New Jersey USA. 2007.

23. Bean WT, Stafford R, Brashares JS. The effects of small sample size and sample bias on threshold selection and accuracy assessment of species distribution models. Ecography. 2012;35: 250–258.

24. Jiménez-Valverde A, Lobo JM. Threshold criteria for conversion of probability of species presence to either–or presence–absence. Acta oecologica. 2007;31: 361–369.

25. Hernandez PA, Graham CH, Master LL, Albert DL. The effect of sample size and species characteristics on performance of different species distribution modeling methods. Ecography. 2006;29: 773–785.

26. R Core Team, 2017. R: A language and environment for statistical computing. Vienna.

27. Meyer MF, Rheubert JL, Charvat R, 2018. Predicting antibacterial activity from snake venom proteomes [WWW Document]. URL

28. Samy RP, Stiles BG, Chinnathambi A, Zayed ME, Alharbi SA, Franco OL, et al. Viperatoxin-II: A novel viper venom protein as an effective bactericidal agent. FEBS Open Bio. 2015;5: 928–941. doi: 10.1016/j.fob.2015.10.004 26793432

29. Abdelkafi-Koubaa Z, Aissa I, Morjen M, Kharrat N, El Ayeb M, Gargouri Y, et al. Interaction of a snake venom L-amino acid oxidase with different cell types membrane. International Journal of Biological Macromolecules. 2016;82: 757–764. doi: 10.1016/j.ijbiomac.2015.09.065 26433175

30. Ozverel CS, Damm M, Hempel BF, Gӧçmen B, Sroka R, Süssmuth RD, et al. Investigating the cytotoxic effects of the venom proteome of two species of the Viperidae family (Cerastes cerastes and Cryptelytrops purpureomaculatus) from various habitats. Comparative Biochemistry and Physiology Part C: Toxicology & Pharmacology. 2019;220: 20–30.

31. Samy R, Pachiappan A, Gopalakrishnakone P, Thwin MM, Hian YE, Chow VT, et al. In vitro antimicrobial activity of natural toxins and animal venoms tested against Burkholderia pseudomallei. BMC Infect Dis. 2006;6: 100. doi: 10.1186/1471-2334-6-100 16784542

32. Ferreira BL, Santos DO, Santos AL, Rodrigues CR, de Freitas CC, Cabral LM, et al. Comparative analysis of Viperidae venoms antibacterial profile: a short communication for proteomics. Evid Based Complement Alternat Med. 2011;2011: 1–4.

33. Yan X, Zhang S, Chang Q, Liu P, Xu J. Antibacterial and antifungal effects of Agkistrodon halys Pallas: purification of its antibacterial protein—LAO. Shi Yan Sheng Wu Xue Bao. 2000;33: 309–316. 12549069

34. Kalita B, Patra A, Mukherjee AK. Unraveling the proteome composition and immuno-profiling of western India Russell’s viper venom for in-depth understanding of its pharmacological properties, clinical manifestations, and effective antivenom treatment. J Proteome Res. 2017;16: 583–598. doi: 10.1021/acs.jproteome.6b00693 27936776

35. Prabhakaran AK, Kumaravel P, Priya J, Melchias G, Edward A, Sridevi G. Investigation of antibacterial and haemolytic activity of Russell’s viper and Echis carinatus venom. Asian J Pharm Anal. 2014;4: 1–4.

36. Rangsipanuratn W, Sandee A, Daduang J, Janwithayanuchit I. Antibacterial activity of snake venoms against bacterial clinical isolates. Pharm Sci Asia. 2019;46: 80–87.

37. Boda FA, Mare A, Szabó ZI, Berta L, Curticapean A, Dogaru M et al. Antibacterial activity of selected snake venoms on pathogenic bacterial strains. Revista Românӑ de Medicinӑ de Laborator. 2019;27: 305–317.

38. Del-Rei THM, Sousa LF, Rocha MMT, Freitas-de-Sousa LA, Travaglia-Cardoso SR, Grego K, et al. Functional variability of Bothrops atrox venoms from three distinct areas across the Brazilian Amazon and consequences for human envenomings. Toxicon. 2019;164: 61–70. doi: 10.1016/j.toxicon.2019.04.001 30991062

39. Nair DG, Fry BG, Alewood P, Kumar P, Kini RM. Antimicrobial activity of omwaprin, a new member of the waprin family of snake venom proteins. Biochem J. 2007;402: 93–104. doi: 10.1042/BJ20060318 17044815

40. Chen LW, Kao PH, Fu YS, Lin SR, Chang LS. Membrane-damaging activity of Taiwan Cobra cardiotoxin 3 is responsible for its bactericidal activity. Toxicon. 2011;58: 46–53. doi: 10.1016/j.toxicon.2011.04.021 21575651

41. Kao PH, Lin SR, Hu WP, Chang LS. Naja naja atra and Naja nigricollis cardiotoxins induce fusion of Escherichia coli and Staphylococcus aureus membrane-mimicking liposomes. Toxicon. 2012;60: 367–377. doi: 10.1016/j.toxicon.2012.04.345 22569319

42. Konshina AG, Boldyrev IA, Utkin YN, Omel’kov AV, Efremov RG. Snake cytotoxins bind to membranes via interactions with phosphatidylserine head groups of lipids. PLoS ONE. 2011;6: e19064. doi: 10.1371/journal.pone.0019064 21559494

43. Lee SC, Lin CC, Wang CH, Wu PL, Huang HW, Chang CI, et al. Endocytotic routes of cobra cardiotoxins depend on spatial distribution of positively charged and hydrophobic domains to target distinct types of sulfated glycoconjugates on cell surface. J Biol Chem. 2014;289: 20170–20181. doi: 10.1074/jbc.M114.557157 24898246

44. Toyama MH, Toyama DO, Passero LFD, Laurenti MD, Corbett CE, Tomokane TY, et al. Isolation of a new l-amino acid oxidase from Crotalus durissus cascavella venom. Toxicon. 2006;47: 47–57. doi: 10.1016/j.toxicon.2005.09.008 16307769

45. Samy RP, Gopalakrishnakone P, Chow VTK, Ho B. Viper metalloproteinase (Agkistrodon halys pallas) with antimicrobial activity against multi-drug resistant human pathogens. J Cell Physiol. 2008;216: 54–68. doi: 10.1002/jcp.21373 18297685

46. Tan CH, Fung SY, Yap MKK, Leong PK, Liew JL, Tan NH. Unveiling the elusive and exotic: Venomics of the Malayan blue coral snake (Calliophis bivirgata flaviceps). J Proteomics. 2016;132: 1–12. doi: 10.1016/j.jprot.2015.11.014 26598790

47. Tan CH, Tan KY, Lim SE, Tan NH. Venomics of the beaked sea snake, Hydrophis schistosus: A minimalist toxin arsenal and its cross-neutralization by heterologous antivenoms. J Proteomics. 2015;126: 121–130. doi: 10.1016/j.jprot.2015.05.035 26047715

48. Rey-Suárez P, Saldarriaga-Córdoba M, Torres U, Marin-Villa M, Lomonte B, Núñez V. Novel three-finger toxins from Micrurus dumerilii and Micrurus mipartitus coral snake venoms: Phylogenetic relationships and characterization of Clarkitoxin-I-Mdum. Toxicon. 2019;170: 85–93. doi: 10.1016/j.toxicon.2019.09.017 31557485

49. Fernández J, Vargas-Vargas N, Pla D, Sasa M, Rey-Suárez P, Sanz L, et al. Snake venomics of Micrurus alleni and Micrurus mosquitensis from the Caribbean region of Costa Rica reveals two divergent compositional patterns in New World elapids. Toxicon. 2015;107: 217–233. doi: 10.1016/j.toxicon.2015.08.016 26325292

50. Shan LL, Gao JF, Zhang YX, Shen SS, He Y, Wang J, et al. Proteomic characterization and comparison of venoms from two elapid snakes (Bungarus multicinctus and Naja atra) from China. J Proteomics. 2016;138: 83–94. doi: 10.1016/j.jprot.2016.02.028 26924299

51. Pla D, Sanz L, Sasa M, Acevedo ME, Dwyer Q, Durban J, et al. Proteomic analysis of venom variability and ontogeny across the arboreal palm-pitvipers (genus Bothriechis). J Proteomics. 2017;152: 1–12. doi: 10.1016/j.jprot.2016.10.006 27777178

52. Calvete JJ, Pérez A, Lomonte B, Sánchez EE, Sanz L. Snake Venomics of Crotalus tigris: The minimalist toxin arsenal of the deadliest neartic rattlesnake venom. Evolutionary clues for generating a pan-specific antivenom against crotalid type II venoms. J Proteome Res. 2012;11: 1382–1390. doi: 10.1021/pr201021d 22181673

53. Tan CH, Tan NH, Sim SM, Fung SY, Gnanathasan CA. Proteomic investigation of Sri Lankan hump-nosed pit viper (Hypnale hypnale) venom. Toxicon. 2015;93: 164–170. doi: 10.1016/j.toxicon.2014.11.231 25451538

54. Lomonte B, Fernández J, Sanz L, Angulo Y, Sasa M, Gutiérrez JM, et al. Venomous snakes of Costa Rica: Biological and medical implications of their venom proteomic profiles analyzed through the strategy of snake venomics. J Proteomics. 2014;105: 323–339. doi: 10.1016/j.jprot.2014.02.020 24576642

55. Pahari S, Mackessy SP, Kini RM. The venom gland transcriptome of the Desert Massasauga Rattlesnake (Sistrurus catenatus edwardsii): towards an understanding of venom composition among advanced snakes (Superfamily Colubroidea). BMC Mol Biol. 2007;8: 115. doi: 10.1186/1471-2199-8-115 18096037

56. Sanz L, Gibbs HL, Mackessy SP, Calvete JJ. Venom proteomes of closely related Sistrurus rattlesnakes with divergent diets. J Proteome Res. 2006;5: 2098–2112. doi: 10.1021/pr0602500 16944921

57. Modahl CM, Mackessy SP. Venoms of Rear-Fanged Snakes: New Proteins and Novel Activities. Front Ecol Evol. 2019;7: 1–18.

58. Fry BG, Scheib H, van der Weerd L, Young B, McNaughtan J, Ramjan SFR, et al. Evolution of an arsenal: structural and functional diversification of the venom system in the advanced snakes (Caenophidia). Mol Cell Proteomics. 2008;7: 215–246. doi: 10.1074/mcp.M700094-MCP200 17855442

59. Kardong K. Colubrid snakes and Duvernoy’s “venom” glands. J Toxicol-Toxin Rev. 2002;21: 1–15.

60. Vonk FJ, Jackson K, Doley R, Madaras F, Mirtschin PJ, Vidal N. Snake venom: From fieldwork to the clinic: Recent insights into snake biology, together with new technology allowing high-throughput screening of venom, bring new hope for drug discovery. BioEssays. 2011;33: 269–279. doi: 10.1002/bies.201000117 21271609

61. Campos PF, Andrade-Silva D, Zelanis A, Paes Leme AF, Rocha MMT, Menezes MC, et al. Trends in the evolution of snake toxins underscored by an integrative omics approach to profile the venom of the colubrid Phalotris mertensi. Genome Biol Evol. 2016;8: 2266–2287. doi: 10.1093/gbe/evw149 27412610

62. Ching ATC, Paes Leme AF, Zelanis A, Rocha MMT, Furtado MFD, Silva DA, et al. Venomics profiling of Thamnodynastes strigatus unveils matrix metalloproteinases and other novel proteins recruited to the toxin arsenal of rear-fanged snakes. J Proteome Res. 2012;11; 1152–1162. doi: 10.1021/pr200876c 22168127

63. Pla D, Sanz L, Whiteley G, Wagstaff SC, Harrison RA, Casewell NR, et al. What killed Karl Patterson Schmidt? Combined venom gland transcriptomic, venomic and antivenomic analysis of the South African green tree snake (the boomslang), Dispholidus typus. Biochim Biophys Acta BBA—Gen Subj. 2017;1861: 814–823.

64. Jansen D. A possible function of the secretion of Duvernoy’s gland. Copeia. 1983: 262–264.

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