If you are a frequent follower of my blog you will know one issue that I am passionate about is antibiotic resistance in pathogenic bacteria. This is a problem that has been slowly creeping up on us all and has the potential to effect many peoples lives in the future if work is not done to solve things sooner rather than later. I have written a few posts in the past where I have discussed various aspects of this issue: (Post 1, Post 2, and Post 3).

This time, lets discuss the work published in the Journal of Proteome Research February 6, 2017 titled "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."

If you have read that title you may have noticed the article is talking about the Komodo Dragon

Yes, this creature!

Well...What Were They Looking At?

They were looking at protein compounds which are a part of the innate immune system called "Cationic Antimicrobial Peptides" or CAMPs.

SIDE NOTE

We have two broad classes of immune response, the innate immune response and the adaptive immune response. The one you are more familiar with, involving killer-T cells, antibodies, B-cells and macrophages which work together to target and destroy invading pathogens is known as the adaptive immune system. It's called adaptive because it can adapt to new invaders and change its specificity to target these new pathogens.

The innate immune system is thought of as our initial line of defense against invaders, and this immune function occurs in a more generalized broad way as it is meant to target a wide variety of potential invaders.

END SIDE NOTE

The reason CAMPs is so effective is that they are relatively small proteins and also their positive charge both of which allow them to target (typically) the cell membrane of a bacterial pathogen (their size and charge also allow them to target a variety of different bacteria non specifically but still remain effective in disrupting the cell wall, killing the cells). Finally, these proteins are attractive candidates for further development into antibiotics as to date there hasn't been much bacterial resistance to them observed.^[4]

But why Komodo Dragons?

Good question, the reason they were studied in the first place is their mouths. In their mouths live quite the assortment of different bacterial organisms (according to the article there are 57 different bacteria living there, and at least 51 of those are pathogenic), however none of these organisms do any harm to the Komodo Dragon. Why is that?

"Because I'm a bad ass dragon that's why" - Komodo Dragon

No, sorry Mr./Ms. Dragon, it's not because you are a bad ass (you are, but that's another matter... _{don't bite me please}). The reason is CAMPs, which circulate in the blood of the Komodo Dragon. An older study done on blood serum (which is the plasma with all of the blood cells removed, so just soluble compounds in the blood) was able to kill bacteria [5]

So Researchers Set Out To Better Understand These Komodo Dragon CAMPs

The researchers used a mass spectrometry based technique to extract information about the sequences of the CAMPs present in samples of Komodo Dragon blood serum, and were able to identify 8 short peptide candidates (and when I say short I mean short! The shortest peptide was 14 amino acids long, while the longest was 27 amino acids). They then tested the 8 candidate peptides against two different bacterial organisms (one gram positive) called Staphylococcus aureus

This is Staphylococcus aureus

(which you may know of as the infective agent from a "staph" infection) and another (gram negative) called Pseudomonas aeruginosa (which doesn't typically cause disease in humans, but serves as a good model for the gram negative class of bacterium).

This is an electron micrograph of Pseudomonas aeruginosa

What Did They Find? Were The Peptides Effective At Killing The Two Types Of Bacteria?

Their control was a human CAMP called "LL-37", and by comparison they found that 3 of the peptides were better at killing the Staphylococcus aureus (I base the term "better" on a lower EC50, aka it took less of the peptide to kill the Staphylococcus aureus then it took of the human CAMP), and another 2 were similar to the human CAMP. However none of the Komodo Dragon CAMPs were better than the human CAMP at killing the Pseudomonas aeruginosa, but 4/8 were similar in efficacy. NOTE ALL of the CAMPS could kill both bacterium, but some of the required concentrations were pretty high.

Where Do These Peptides Come From?

The researchers stated that they are all derived from parts of histone proteins. If you recall from a post of mine on epigenetic regulation, we discussed histones. Briefly these are proteins involved in the process of DNA compaction that allows the very long genome to be squished together into chromosomes. Histones are the proteins that make up the nucleosome, which is a particle that the DNA spools around (like thread) allowing for the first level of compaction.

The researchers also cite an old paper describing the ability of histone proteins to kill bacteria.^[6]. More recently, excess histone proteins (those not involved in DNA compaction) have been observed to be a cellular defense mechanism, being released by cells upon bacterial infection.^[7]. So there is precedence in the literature for histones being involved in killing bacteria (TIL!).

Based upon this, it should perhaps not be surprising that these short peptides utilized as a defense mechanism by the Komodo Dragon innate immune system are small pieces of histone proteins. Perhaps Komodo Dragons do not use the same mechanism of whole histone proteins for defense like was shown in the above cited article for flies, but rather these small peptides are the active agent performing a similar function.

TL;DR

Proteomics work studying small positively charged protein fragments (CAMPs) present in the blood of the Komodo Dragon were observed to have bacteria killing properties. These short protein fragments all are derived from histone proteins (surprisingly) which are proteins involved in compacting the cells genome into chromosomes. These proteins also have anti-bacterial activities for the cell (as observed in flies), however it is uinque to see these short peptides derived from them. These are the only CAMPs ever observed to come from the histone proteins, and their anti-bacterial properties illustrate their potential to be developed as a new form of antibiotic for potentially treating antibiotic resistant bacteria such as MRSA.

Hopefully continued work will go into promising results such as these and we will have a nice, straightforward solution to the growing antibiotic resistant bacteria problem before things get out of hand. These sorts of new discoveries could be the key to saving many lives in the coming decades and I know that I personally at least, will be closely watching for additional new developments.

Sources

1. http://pubs.acs.org/doi/abs/10.1021/acs.jproteome.6b00857
2. https://en.wikipedia.org/wiki/Antimicrobial_peptides
3. https://en.wikipedia.org/wiki/Innate_immune_system
4. https://www.ncbi.nlm.nih.gov/pubmed/19451641
5. https://www.researchgate.net/publication/273314383_Antibacterial_activities_of_serum_from_the_Komodo_Dragon_Varanus_komodoensis
6. https://www.ncbi.nlm.nih.gov/pubmed/13598820
7. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3490148/

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