Wednesday, February 8, 2012

1 Memo: Borrelia Are NOT Gram-Negative Bacteria, And Might Become Resistant

For years, Borrelia have been thought to be Gram-negative because of their diderm and structural appearance upon staining. Borrelia - including Borrelia burgdorferi - are not Gram-negative bacteria, though - even though many people are still referring to them as such. They belong in their own category.

As I was telling Dr. MacDonald this week:
I found information confirming the fact that Borrelia is not Gram-negative or Gram-positive. It's its own special thing:

"Borrelia were thought to be Gram negative because of their double membrane structure, but genetic analysis places them - along with other spirochetes - into a separate eubacterial phylum. Ultrastructural molecular and biochemical studies have emphasized the wide taxonomic gap between spirochetes and Gram-negative bacteria."

- From "The Genus Borrelia" by Melissa Caimano. Prokaryotes (2006) 7:235-293.

"Although Borrelia spirochetes are often, but mistakenly described as Gram-negative bacteria due to their diderm, i.e. double-membrane envelopes, a closer examination reveals significant differences in composition and architecture. Probably most striking is the lack of LPS, the presence of major surface lipoproteins at the host-pathogen interface during transmission, persistence and ensuing pathogenic processes and the additional function of periplasmic flagella in defining cell shape. While surface lipoproteins such as the Osps interact with a variety of ligands in different organ tissues, they are also targets of the immune response and several have emerged as vaccine candidates."

- From Borrelia: Molecular Biology, Host Interaction and Pathogenesis. Edited by D. Scott Samuels and Justin D. Radolf. (2010)

So one could say they are Gram-negative-"like" - but strictly speaking, Borrelia is not Gram-negative bacteria."
He accepted this response, and is now stating that Borrelia burgdorferi is Gram-indeterminate.

There is additional information from the second source cited which indicates that Borrelia spirochetes are different from other bacteria, summarized here:
"Some of the identified periplasmic lipoproteins, i.e. the OppAs, are components of substrate transport complexes. Investigations into integral membrane proteins led to the identification of several Borrelia porins: P13, whose structure and function is unknown, DipA, which is specific for dicarboxylates and P66 (Oms66), which has a dual role as a pore-forming outer membrane protein with an extremely high single channel conductance and an adhesin for β3-integrin. The recently identified Tol homologs BesA, -B and -C appear to form a Type I 'channel' to export exogenous toxic agents such as antibiotics and to maintain infectivity by an unknown mechanism. Initial studies on envelope biogenesis pathways based on diderm proteobacterial model organisms already revealed significant deviations from the norm. This further bolsters the unique status of Borrelia among microbial pathogens."
Damn Borrelia... Why do you have to be such a deviant? Why can't you just conform?

Anyway, the Type I 'channel' they're talking about above which exports or removes antibiotics and helps maintain infectivity is said here to do so using an unknown mechanism. Judging from research out there, this channel relates to transmembrane proteins which span the outer and inner membranes of the bacteria - and it appears to function like an efflux pump (in this case, a resistance-nodulation-division-like pump) which removes antibiotics and is involved in antibiotic resistance. Check out this paper (full text at link):

Source: http://www.plospathogens.org/article/info%3Adoi%2F10.1371%2Fjournal.ppat.1000009

An RND-Type Efflux System in Borrelia burgdorferi Is Involved in Virulence and Resistance to Antimicrobial Compounds

Ignas Bunikis1, Katrin Denker, Yngve Östberg1, Christian Andersen, Roland Benz, Sven Bergström. PLoS Pathog. 2008 Feb 29;4(2):e1000009.

Abstract

Borrelia burgdorferi is remarkable for its ability to thrive in widely different environments due to its ability to infect various organisms. In comparison to enteric Gram-negative bacteria, these spirochetes have only a few transmembrane proteins some of which are thought to play a role in solute and nutrient uptake and excretion of toxic substances. Here, we have identified an outer membrane protein, BesC, which is part of a putative export system comprising the components BesA, BesB and BesC. We show that BesC, a TolC homolog, forms channels in planar lipid bilayers and is involved in antibiotic resistance. A besC knockout was unable to establish infection in mice, signifying the importance of this outer membrane channel in the mammalian host. The biophysical properties of BesC could be explained by a model based on the channel-tunnel structure. We have also generated a structural model of the efflux apparatus showing the putative spatial orientation of BesC with respect to the AcrAB homologs BesAB. We believe that our findings will be helpful in unraveling the pathogenic mechanisms of borreliae as well as in developing novel therapeutic agents aiming to block the function of this secretion apparatus.



Obviously, more research in this direction is necessary.

So when people ask, "Camp, why are you so interested in learning about something like TolC? Why don't you want to learn about different kinds of treatment and how they've helped patients?" my answer for them is this:

I do want to learn about different kinds of treatment - it is in my best interest to do so, given I have been dealing with Lyme-related health problems for years. And I make my own decisions about treatment which are largely personal to my situation.

But learning this stuff - these details tucked away in what must appear to most people to be obscure publications in little-known journals outside of researchers within the field? To me, this stuff is what may get us all closer to better treatment for many people.

Do I know this for sure? No. No one does. But with some of the specifics under my belt, I can then at least petition the science world and advocate for the funding to do research on some very particular subjects to get very specific knowledge. Knowledge which may give us a solid idea as to how to treat chronic Lyme disease so that it doesn't become chronic.


1 comment:

  1. There are several papers on efflux pump inhibitors from natural sources. I've found some interesting ones.

    Here's an interesting read.

    http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3100400/pdf/nihms-280725.pdf

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