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Capnine - biofilm bacteria's dirty little secret
 Moderated by: Prof Trevor Marshall  

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Prof Trevor Marshall
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 Posted: Thu Jun 7th, 2007 16:54

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Some months ago we finished our gene-transcriptional description of the Vitamin D metabolism. It was immediately obvious that there was only one mechansim of bacterial action which would give the clinical effects we were observing - and also shut off transcription of the Cathelicidin and beta-Defensin anti-microbial peptides (AMPs).

Shutting down the AMPs is important to the pathogens, for while AMPs are being produced by the phagocytes there will be no persistent pathogens - they will be phagocytosed to fragments of DNA, rather than survive as persistent organisms...

The required mechanism was that the bacteria needed to block the proper functioning of the VDR by producing a ligand which would displace 1,25-D from the VDR binding pocket. In turn, Olmesartan would displace the capnine, at least partially...

I was asked how we could search the bacterial genomes and identify the ligand/chemical which the bacteria might produce to block the action of the VDR, and I responded that it would be like searching for a needle in a haystack.

Well, I was wrong. Pasteur's law struck again, and I now have isolated at least one nanomolar-grade (strong) antagonist which is formed by a special type of bacteria which like to live in biofilms, and which are very poorly studied, and almost impossible to culture.

The breakthrough came when I started to look at a recent paper on some strange bacteria which had been isolated from biofilms on prothestic joints. As you know, I have a complete disease model now, so I understand exactly where prostheses fit in the overall scheme of things, and I understand that healthy folk are just sick folk whose bacterial load has not yet made them very ill :) So it was with that jaundiced eye I read this paper:

"Identification of bacteria on the surface of clinically infected and non-infected prosthetic hip joints removed during revision arthroplasties by 16S rRNA gene sequencing and microbiological culture"
http://tinyurl.com/2hqojq  PMID: 17501992

I immediately knew we had something very important here, and when I researched these special "gliding" bacteria, which move by gliding, perhaps like a snail, rather than by whipping flagella like the common blood-borne bacterial species, I realised we had hit mother-lobe.

Associated with the gliding motion is a unique lipid called capnine, a highly charged lipid, and one which is a strong inhibitor (antagonist) of VDR transcriptional activity.



It really doesn't matter whether these gliding bacteria harm the body in any other way, by shutting down the AMPs they create an environment where a plethora of other bacteria and viral pathogens can weave their nasty ways upon the host.

Here is a Real-Format video of my molecular dynamics simulation of capnine in the VDR LBP, showing an exceptionally stable dynamic configuration. Its action as an antagonist is confirmed by the LBP expanding in size during the entire period of the simulation, and losing the configuration in which it can bind to the DRIP205 coactivator and transcribe the AMP genes.

http://autoimmunityresearch.org/models/capnine-vdrh.ram

So now the model is complete.
We know what pathogens can cause Th1 disease, and they were discovered purely by mathematical deduction, and not by looking into petrie dishes... or harming any furry animals:)

So where do we go from here? I had thought of making a big song and dance and trying to persuade a journal to publish this stuff. But that would be a complete waste of our time. At this point we have to start focusing on 'saving the world' not on being ''first to publish.' So there it is .. an almost complete glimpse of the grail...

----------------------------------------

All above content (C)Copyright 2007 Trevor G Marshall, All Rights Reserved.

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 Posted: Thu Jun 7th, 2007 18:01

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Awesome work Prof M!! Congratulations :D:D.



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kathleen
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 Posted: Thu Jun 7th, 2007 18:19

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It's totally incredible to be witness to such a huge breakthrough. I can't even think of what to say except for Thank You.

And thank you again for not wasting energy trying to convince tptb, but getting on with learning more about how to help people get better. Like me for instance!!

XXOOO Kathleen



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Frans
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 Posted: Thu Jun 7th, 2007 18:26

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Wow Trevor ! This is cool !

Now, all we need is a drug that takes care of this capnine and we are home free  :D

But seriously, I understand from what you say, that you have also found which other species can make this capnine?

Am I correct in assuming that capnine is one of the proteins/things bacteria fabricate and we are effectively stopping them from doing that by sabotaging their ribosomes?

Or is it something other than the ribosomes that make capnine?

And going further even, have you perhaps found if the gene(s) that is (are) responsible for this is horizontally transmittable between species?

Just some things that are popping into my mind at this point :)

Sincerely, Frans



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Prof Trevor Marshall
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 Posted: Thu Jun 7th, 2007 18:33

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Frans,
The Ribosomes only make proteins. This is a lipid, and a highly processed lipid. Enzymatic activity is what creates it. That is why a full-genome search is futile - gene transcription analysis doesn't take into account the enzymatic actions.

However, enzymes start as complex proteins, and so by blocking the ribosomes we block the ability of the bacteria to form capnine.
 

Ruth Goold
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 Posted: Thu Jun 7th, 2007 21:07

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Trevor,

Congratulations on an amazing discovery.  I agree that functional genomics would have been a very much slower way of identifying capnine as the VDR anatagonist, but now that you have done the hard work :) I don't think it should take long to identify the genes involved in capnine production.  Fascinating possibilities here to study host-pathogen interactions in human cell lines.  Consider the following information a cursory search shows up in identifying some Lysobacter genes involved in the production of antimicrobials (in a fungal host):

A global regulator was previously identified in Lysobacter enzymogenes C3, which when mutated, resulted in strains that were greatly reduced in the expression of traits associated with fungal antagonism and devoid of biocontrol activity towards bipolaris leaf-spot of tall fescue and pythium damping-off of sugarbeet. A clp gene homologue belonging to the crp gene family was found to globally regulate enzyme production, antimicrobial activity, and biological control activity expressed by Lysobacter enzymogenes C3 (Kobayashi et al. 2005).  

From: Kobayashi and Yuen.  2005. The role of clp-regulated factors in antagonism against Magnaporthe poae and biological control of summer patch disease of Kentucky bluegrass by Lysobacter enzymogenes C3.  Can. J. Microbiol. 51:719-723.

I think things will start progressing very quickly (should I say, even more quickly)now on the genetics/genomics front.

One question: capnine seems like a very specialized molecule (or a perhaps quite an ordinary lipid with a very specialized function) (chemists on board care to comment?) - do you think it is more likely one-of-a-kind or one-of-many in its VDR antagonism capbability?

Many thanks,

Ruth  



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Prof Trevor Marshall
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 Posted: Thu Jun 7th, 2007 21:39

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Ruth,
I think it is one-of-a-kind, a very special molecule.

I have been alert to the close symbiosis between the retinoids and Vitamins D for some time. For example, either can function to hold together COMP, and both are active in Rhodopsin, but the retinoids have a relatively low Ki for the VDR. When Capnine popped up the similarity in size and shape immediately struck me...

I was particularly intrigued by the "pea-soup" possibilities for the Lysobacters, as they produce toxins targeted at both both fungal and bacterial 'partners.' For example, one study showed that Lysobacter killed e-coli colonies, but not e-coli colonies which had been infected by the T4 bacteriophage.

http://tinyurl.com/2b9pdm PMID: 4927527
 

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 Posted: Thu Jun 7th, 2007 21:48

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I'd also like to say congratulations to you Dr. Marshall.  I see from your response above that capnine seems to be a one-of-a-kind molecule rather than one of many.  Do you also think that the bacteria you identified as producing it is one-of-a-kind or do you think there might be many bacteria that produce it or is that not known yet?



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Prof Trevor Marshall
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 Posted: Thu Jun 7th, 2007 22:01

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Russ,
There may indeed be many viable VDR-antagonist-ligands that have evolved with differing species over time, or capnine may be the only one. We just don't know yet.

However, from a scientific point of view, we have one candidate, in a viable bacterial family, and therefore we can move forward exploring those avenues of the pathogenesis in more detail.

I would note that there are more than one species of gliding bacteria, and that capnine seems common to many of the species of gliding bacteria.

http://tinyurl.com/2zac8w  PMID: 6321489
 

Ruth Goold
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 Posted: Thu Jun 7th, 2007 22:48

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Actually, our good friends the Mycoplasma, long known to be associated with chronic inflammatory conditions are gliding bacteria:

Mycoplasmas are bacteria that lack a cell wall and are parasitic or commensal to many kinds of hosts, including humans, animals, and plants.

In addition, the gliding motility of mycoplasmas is believed to be involved in their pathogenicity and a number of proteins required for adhesion to host cells and gliding have been identified.  I think it has been more or less assumed that the loss of pathogenicity associated with mutations in these proteins is due to the reduced ability of the bacteria to attach to or penetrate the host cells, but maybe these mutants also have reduced abiltiy to produce capnine.

Oh indeed, speculation is good fun ... 

Ruth



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 Posted: Thu Jun 7th, 2007 23:54

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Congratulations. So this is a compound present in bio-film. I wonder if there are databases about chemical structures of bio-films, so they could be tested for vdr affinity.



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 Posted: Fri Jun 8th, 2007 01:21

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Hooray, dear Trevor 
 
Even if you do not want to dance, let me dance in joy and deep admiration for your amazing, breathtaking and pathbreaking work 
 
I celebrate with you 
 
I am overjoyed 
 
Evelin

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 Posted: Fri Jun 8th, 2007 10:20

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Push the button to play the movie

Last edited on Fri Jun 8th, 2007 10:22 by wrotek



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 Posted: Fri Jun 8th, 2007 16:43

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Dr. Marshall,

Amazing work...

My concern: can patients with prosthetic joints succeed with the MP? Seems a likelihood of another continuous source of infection. Today it is so common to hear of joint replacement surgery.

Any comments appreciated!

Mary



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Prof Trevor Marshall
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 Posted: Fri Jun 8th, 2007 16:46

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Mary,
As long as the folk use the MP tp work down their bacterial load to levels of the general population, they will have as much success with prostheses as 'normal' folk do, and a lot less trouble than many folk do :)

The issue here is not prostheses, I am sure that normal joints would have shown similar bacterial populations, it is just that normal joints don't often become available for such a study, whereas prostheses do...

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 Posted: Fri Jun 8th, 2007 17:37

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Dr. Marshall,

This work is brilliant, and I count myself as very fortunate to read it. 

Now my peasant mind is thinking that Benicar is snail bait (LOL).

With the identification of capnine, is it possible that a better drug might be found?  Is capnine found in any specific foods?  I consulted the USDA Nutritional database, but found nothing.

With deep thanks,

Sherry



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Prof Trevor Marshall
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 Posted: Fri Jun 8th, 2007 20:07

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Sherry,
Capnine is uniquely made by gliding bacteria.

If capnine turns out to be the only bacterial product which blocks the VDR, you really don't want to try and target this with a drug. If you did neutralize the capnine, you would end up with an immune system that is suddenly freed to attack ALL of the pathogenic load at once.

Think about it - you are using just enough antibiotic to kill a few bugs every day. Imagine if suddenly your immune system was returned to 'normal' and started attacking all the bugs, all at once. You would become very ill indeed. Probably you would die.

So we need to be careful what we wish for :):):)

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 Posted: Fri Jun 8th, 2007 20:35

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Remember this?

http://en.wikipedia.org/wiki/TGN1412

What a disaster. And they were "healthy" volunteers. Imagine the effect on a th1 patient :shock:.



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 Posted: Fri Jun 8th, 2007 21:00

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Pat,

That is quite telling when the study says that it caused catastrophic system failure in spite being used at "some 500 times lower than the dose found safe in animals".

No doubt most animals did not have a latent pathogen load anywhere near what long-lived human subject would have had. (Especially of course Mice -- here today -- gone next year).

Maybe some day TGN1412 will be harnessed for good.  That would be something.

jim

 



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 Posted: Fri Jun 8th, 2007 21:02

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Dr Trevor Marshall wrote: Mary,
As long as the folk use the MP tp work down their bacterial load to levels of the general population, they will have as much success with prostheses as 'normal' folk do, and a lot less trouble than many folk do :)


This reminded me of a question I have had for a while.  Is it primarily the bacterial load, i.e. the quantity of bacteria, that separates "normal", "healthy" individuals from those of us that are "sick"?  Or are those of us who are sick infected with especially nasty species/strains of bugs that are integrated into our bacterial pea-soup but absent from the bacterial population of "normal", "healthy" folks?

Last edited on Fri Jun 8th, 2007 21:06 by Russ



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