Using dragons blood to fight antibiotic resistance

Antibiotic resistance is one of the biggest threats facing the modern world. Frivolous prescriptions and largescale agricultural usage had led the world to the brink of a post antibiotic age. Such a world harks back to Victorian times, people dying from infected cuts, routine operations becoming a thing of the past and long forgotten diseases, such as tuberculosis, becoming commonplace. As you might imagine there has been a huge scientific response to try and establish new ways to kill bacteria before antibiotics become obsolete. This has ranged from the discovery of new antibiotics (Ling et al., 2015) to using other forms of bacteria to kill the pathogens (Tyson & Sockett, 2017). A new paper published in The Journal of Proteome Research by Bishop et al. (2017) suggests that they may have found another method, dragons blood. Not the mythical winged beasts with a penchant for dwarfish gold, but the closest real world equivalent, the Komodo dragon.

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Figure 1: A Komodo dragon (Varanus Komodoensis). Taken from: https://goo.gl/images/kPEqh0

 

It is a popular urban myth that Komodo dragons use bacteria in their mouths as a form of venom. The story goes that if an animal is bitten by a Komodo dragon but escapes, they will eventually die from the wound as bacteria within the dragons mouth will infect and kill the animal. Scientists have since discovered that the beasts have venom glands and surprisingly kill their victims with venom (who would have thought?) (Fry, et al., 2009). However, while the bacteria in the dragons mouths are not responsible for killing, a broad spectrum is present in saliva, the vast majority of which can be considered ‘potentially pathogenic’ (Bishop et al. 2017). So how do Komodo dragons quite happily live with these pathogenic bacteria in their saliva without any signs of infection? Especially as frequent fighting between dragons includes biting, but battle wounds hardly ever lead to infection. This led scientists to look at the immune system of the Komodo dragon.

Bishop et al. specifically looked at cationic antimicrobial peptides (CAMPs) in the dragons blood plasma. These peptides are an essential part of the immune system and are found in nearly all living organisms. They function as part of the innate immune system (that which is present from birth). They appear to work by directly interacting with pathogens as the body’s first line of defence. They target the lipopolysaccharide (LPS) layer of bacterial cell membranes. Some have even been found to enhance the effect of antibiotics (Bahar and Ren, 2013). CAMPs have displayed effectivity against bacteria, viruses and fungi. These molecules are conserved across evolution but hardly any bacterial resistance has been observed. For these reasons scientists have increased research into CAMPs in recent years. Bishop et al. designed a new method for extraction and identification of CAMPs from the Komodo dragon plasma, deemed ‘bioprospecting’, that is faster and more efficient than previous methods.

Firstly, CAMPs were harvested from blood plasma. Plasma was used that had been stimulated by incubating it with LPS, as the presence of bacterial cell markers has been shown to increase the production of CAMPs in blood plasma. Unstimulated blood plasma was also used. The process by which this occurred is illustrated in Figure 2. The particles were then analysed using complex mass spectrometry. Peptides that had no match to databases were looked at further to see if they contained DNA sequences and chemical properties related to CAMPs with known antimicrobial properties (i.e. similar pH, hydrophobicity, size). To do this a computer script was created using the coding programme PYTHON, it was this step that reduced analysis of potential target molecules from weeks to a matter of minutes.

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Figure 2: How CAMPs were separated from blood plasma. A) Hydrogel particles were added to the plasma. B) The particles attract all the small cationic peptides in the plasma but exclude larger proteins. C) The particles are purified from the sample D) and eluted to remove the hydrogel particles. E) the peptides are sequenced. Taken from Bishop et al., 2015

 

Bishop et al. found 48 potential new CAMPs using this method. All but one were histone derived proteins. Histones are proteins that are involved with condensing chromatin so that chromosomes fit within a cells nucleus, they also play a role in gene activation. Research has been published showing that histones might also have antimicrobial properties (Hirsch, 1958). Findings align with previous publications and suggests that further research is needed into the antimicrobial properties of histones and their derivatives. The antimicrobial properties of 8 out of the 48 potential CAMPs were tested against two different types of potentially pathogenic bacteria, Pseudomonas aeruginosa, which is gram negative, and Staphylococcus aureus, which is gram positive.  Seven of the peptides were effective antimicrobials against both bacteria, the 8th CAMP was only effective against P. aeruginosa.  

These results open the door to further study into the antimicrobial properties of CAMPs. Such research is especially promising as plasma from other species of animal may be host to a whole different range of CAMPs. This would mean that if resistance were to develop, a new drug with a different CAMP could be used to treat infections. This is no panacea but, as scientists have started to realise, bacteria will always develop resistance to antimicrobials. The trick is to keep developing compounds to combat them and stay one step ahead. While this research is still a long way from creating drugs based on these CAMPs, it is not impossible that one day we may be taking pills with extract of dragon blood to help fight infections.

References

Bahar, A.A. and Ren, D. (2013) Antimicrobial Peptides. Pharmaceuticals 6, 1543-1575

Bishop, B.M., Juba, M.L., Devine, M.C., Barksdale, S.M., Rodriguez, C.A., Chung, M.C. et al. (2015) Bioprospecting the American alligator (Alligator mississippiensis) host defense peptidome. Public Library of Science One 10, 1-17

Bishop, B.M., Juba, M.L., Russo, P.S., Devine, M., Barksdale, S.M., Scott, S. et al. (2017) Discovery of novel antimicrobial peptides from Varanus komodoensis (Komodo Dragon) by large-scale analyses and De-Novo-Assisted sequencing using electron-transfer dissociation mass spectrometry. Journal of Proteome Research

Fry, B.G., Wroe, S., Teeuwisse, W., Van Osch, M.J.P., Moreno, K., Ingle, J. (2009) A central role for venom in predation by Veranus komodensis (Komodo Dragon) and the extinct giant Varanus (Megalania) priscus. Proceedings of the National Academy of Sciences 106, 8969-8974

Hirsch, J.G. (1958) Bactericidal action of histones. The Journal of Experimental Medicine 108, 925-944

Ling, L.L., Schneider, T., Peoples, A.J., Spoering, A.L., Engles, I., Conlon, B.P. et al. (2015) A new antibiotic kills pathogens without detectable resistance. Nature 517, 455-459

Tyson, J. and Sockett, E.R. (2017) Nature knows best: employing whole microbial strategies to tackle antibiotic resistant pathogens. Environmental Microbiology Reports 9, 47-49

https://goo.gl/images/kPEqh0 Last accessed: 5/3/17

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