Fw: [InfectionAndInflammation] is this the one? Bb: primed for drug resistance?

[Guest guest]

,

Found this one, but not sure if this is what you are looking for. Hope it helps.

Donna in NC

[infectionAndInflammation] Bb: primed for drug resistance?

In post # 13639 I raised the issue of drug resistance, and

pointed out that low dose Flagyl/Tini induces mutations within

bacterial genomes and that this can facilitate the acquisition of

resistance not only to Flagyl/Tini but to other antibiotics as well.

This paper:

http://tinyurl.com/6x4p2

says that it takes more than 128 mcg/ml to kill motile

spirochetes. This suggests that motile spirochetes may

express low levels of nitroreductases. Since this concentration

cannot be achieved clinically, exposing motile spirochetes to

" high " doses (i.e., a concentration that is effective against cysts)

of Flagyl/Tini is, in effect, to expose them to low doses. And low

doses are mutagenic and can facilitate the acquisition of drug

resistance, as I've discussed before. Even if your Flagyl/Tini

doses are high enough to destroy cysts but not free spirochetes,

the free spirochetes may well be accumulating mutations. Most

mutations harm fitness. But a lucky fraction of the borrelia

population may gain antibiotic resistance.

One way to combat this problem is by using a variety of

antibiotics. While one bacterium may become genotypically

resistant to, say, rifampin and another bacterium may become

resistant to, say, clarithromycin, a rifampin/clarithromycin combo

will kill both bacteria.

Some microbes have a way around this problem: recombination

and reassortment.

The influenza virus, for example, has a segmented genome.

When two different strains co-infect the same cell the progeny

virions inherit some of their segments from one parent and the

other segments from the other parent. This is reassortment.

Retroviruses co-package duplicate strands of RNA. If two

different strains of HIV-1 co-infect the same cell, some of the

progeny virions will have one genomic copy from one strain and

the other copy from the other strain. Recombination between the

two co-packaged copies creates a chimeric proviral genome.

Here is a good paper on this if you're particularly interested in it:

http://tinyurl.com/5oozu

If one parent HIV-1 encodes resistance to one drug and the other

parent encodes resistance to another drug, recombination can

join the two resistance " loci " on to the same strand of RNA in

their progeny. In this case, the progeny would be resistant to

both drugs. The combo would fail.

It appears that the agent of Lyme disease is designed to take

advantage of reassortment and recombination to a degree that

few bacteria can match. Many bacteria have their genomes

encoded on a single, large strand of DNA. Bb's genome,

however, is highly segmented (broken up into smaller pieces of

DNA):

http://tinyurl.com/4z2lo

It has more than 20 segments (apparently this is unmatched by

any other known bacterium). The main advantage of segmented

genomes is, to my knowledge, the ability to exchange the

segments with different strains. The fact that Bb encodes its

genome on so many segments suggests that it deliberately

swaps those segments when two different strains co-infect the

same host.

Here is recent evidence of that:

http://tinyurl.com/5hmcd

Some quotes from the full-text:

" The discovery of genome-wide genetic exchange among local

B. burgdorferi clones suggests that new adaptive features, such

as its human virulence, could emerge quickly..

Recombination is a powerful facilitator of species adaptation.

Rare beneficial alleles are more likely to be fixed in a population

by avoiding " Muller's Ratchet " , the mutational meltdown and

rapid fitness loss of an asexual species. More important,

beneficial combinations of alleles among loci can arise quickly

through random genome assortment. "

This suggests to me that Bb might achieve multi-drug resistance

in a single patient. Borrelia cells within the population may

reassort/recombine their respective drug resistances into single

cells/genomes thereby creating cells that are resistant to

multiple drugs. And the mutagenicity of Flagy/Tini may facilitate

the creation of the resistance alleles in the first place.

Do any of you Lyme veterans know of testimony consistent with

this? Are there patients who have used antibiotics successfully,

relapsed, and then found that some or all of those antibiotics

weren't effective the next go around?

Matt