The Corpus Callosum

This
is kind of a rambling rehash of an old href="http://corpus-callosum.blogspot.com/2004/03/multidrug-resistant-tb-lessons-about.html">post.
 But it turns out to be topical now.  What is more it
illustrates some interesting points about evolution: some obvious,
others subtle.  One thing is shows very nicely is that once
nature solves a problem, the same solution keeps cropping up in other
places.  

On March 16, 2004, the World Health Organization released a report on
multidrug-resistant tuberculosis.  This is a serious problem,
especially in the former Soviet states of eastern Europe. 
This is
an example of a trend in world health: more and more often, we are
seeing infections caused by bacteria that are able to resist treatment
with antibiotics.  A lot has been written about the topic, so
I
will not discuss the more fundamental aspects of the problem. 
See
this
article
  for a good background review of antibiotic
resistance, and href="http://www.who.int/health_topics/tuberculosis/en/">this
site
for basic information about TB.  Derek Lowe on href="http://www.corante.com/">Corante 
has a detailed href="http://www.corante.com/pipeline/20040301.shtml#72215">explanation. 
Blogger comments are here: href="http://www.ahawkins.org/mt/archives/000470.html">1  href="http://www.jordoncooper.com/2004_03_01_archives.html#107947805833631157">2
href="http://denbeste.nu/cd_log_entries/2004/03/Partialcures.shtml">3

I often hear people say that infectious disease is one of the more
straightforward kinds of illness to understand and to treat. 
Well, simplicity is relative… 


Compared
to something like
rheumatoid arthritis, most infectious disease are simple.  But
this apparent simplicity is deceptive.  Take the example of
tuberculosis.  TB is caused by a kind of bacterium, style="font-style: italic;">Mycobacterium tuberculosis. 
People are not supposed to have  these bacteria growing in
them.  When they do, they are sick.  The sickness is
treated
by giving a chemical that kills the bacteria.  Seems
simple. 
It turns out, though, that the battle between us and TB has been going
on for some time.  Both adversaries have developed
sophisticated
means to try to outwit the other.  The whole topic is
incredibly
complex, but to illustrate, I cite the following article:

style="margin-left: 40px; font-style: italic; color: rgb(153, 0, 0);"> face="Helvetica, Arial, sans-serif"> href="http://www.sciencedaily.com/releases/2001/07/010716112628.htm">Researchers
Find How Tuberculosis Bacterium Evades Detection By Immune System
Sciencedaily.com
7/16/01

A new study published in the July 15 issue of the “Journal of
Immunology” may unlock a door in the search for a vaccine. The study
from Case Western Reserve University’s School of Medicine and
University Hospitals of Cleveland details how the tuberculosis
bacterium evades detection by the body’s immune system.

[…] When an infection invades the body, the immune system is called
upon to
control and stop the infection. Important soldiers in the war against
infection are scavenger cells called macrophages which chew up invading
bacteria and deliver pieces of them to white blood cells named CD4 T
cells.

style="margin-left: 40px; font-style: italic; color: rgb(153, 0, 0);"> face="Helvetica, Arial, sans-serif">Macrophages
have a specialized set of molecules, called MHC-II
(which stands for class II major histocompatibility complex). This set
of molecules is used to present the pieces of invading bacteria to CD4
cells. These pieces, called antigens, are the way CD4 cells can
recognize and eliminate invading bacteria.

style="margin-left: 40px; font-style: italic; color: rgb(153, 0, 0);"> face="Helvetica, Arial, sans-serif">The
CWRU/UHC researchers have discovered that the TB bacterium stops
the immune system from using this important piece of equipment from its
arsenal. The bacterium inhibits the specialized MHC-II molecules by
taking up residence in the macrophages and making a large protein in
abundant quantities which interferes with MHC-II production.

face="Helvetica, Arial, sans-serif"> style="font-style: italic;">Furthermore, the bacterium does
this while
engaging a macrophage
receptor normally used for protection against a large number of
infectious diseases. By employing that receptor and inhibiting MHC-II
molecules, the bacterium evades detection.


Even before the introduction of antibiotics, TB evolved a mechanism to
evade detection by the human immune system.  As soon as
antibiotics were introduced, TB began evolving in ways that cause the
antibiotics to become less effective.  Naturally, this is an
alarming development, one that poses a problem begging for a
solution. 

To attempt to solve this problem, the first temptation is the Tool Time
Method: “more power.”  That is, develop a second antibiotic
that
is stronger that the first one.  Generally, this is done by
generating a zillion new molecular entities and testing them, one by
one, to see how effectively they kill the bacteria.  The
problem
with this approach is that it, too, will fail eventually.  The
bacteria can evolve faster than we can develop new drugs, at least
using the trial-and-error approach.  Thus, the Tool Time
approach
will, at best, buy us a little more time:

style="font-style: italic; margin-left: 40px; color: rgb(153, 0, 0);"> face="Helvetica, Arial, sans-serif"> href="http://www.who.int/mediacentre/releases/2004/pr17/en/">Drug
resistant tuberculosis levels ten times higher in Eastern Europe and
Central Asia
WHO Global Report

style="font-style: italic; margin-left: 40px; color: rgb(153, 0, 0);"> face="Helvetica, Arial, sans-serif"> class="copy">16 MARCH 2004 | GENEVA — Tuberculosis
patients in parts of Eastern Europe and Central Asia are 10 times more
likely to have multidrug-resistant TB (MDR-TB) than in the rest of the
world, according to a World Health Organization (WHO) report into the
deadly infectious disease. China, Ecuador, Israel and South Africa are
also identified as key areas.

[…] MDR-TB is TB that is resistant to the two medicines most commonly
used to treat it, Isoniazid and Rifampicin. Without the correct drugs
MDR-TB is untreatable and in most cases fatal. Though curing ‘normal’
TB is cheap and effective – a six month course of medicines costs US$
10 – treating drug resistant TB is a hundred times more expensive. Even
then a cure is not guaranteed. With no effective vaccine, everyone is
vulnerable to infection simply by breathing in a droplet carrying a
virulent drug resistant strain.

face="Helvetica, Arial, sans-serif">

face="Helvetica, Arial, sans-serif"> style="font-style: italic; color: rgb(153, 0, 0);">[…]
WHO’s leading
infectious disease experts
estimate there are 300 000 new cases per year of MDR-TB worldwide.
There is also new evidence proving drug resistant strains are becoming
more resistant, and unresponsive to current treatments. 79% of MDR-TB
cases are now “super strains”, resistant to at least three of the four
main drugs used to cure TB.

The
second strategy is to figure out how the bacteria are overcoming
our first strategy.  That involves studying, on a molecular
level,  how the bacteria become resistant to
antibiotics. 
This takes a bit of effort, but it is possible to do it because the
bacteria are simple structurally, compared to humans:



face="Helvetica, Arial, sans-serif"> href="http://www.cdc.gov/ncidod/eid/vol4no2/rattan.htm"
style="font-style: italic; color: rgb(153, 0, 0);">Multidrug-Resistant
Mycobacterium tuberculosis: Molecular Perspectives
Emerging
Infectious diseases, Vol 4, No. 2 April-June 1998

Ashok
Rattan,
Awdhesh Kalia, and Nishat Ahmad
style="font-style: italic; color: rgb(153, 0, 0);">
All
India
Institute of Medical Sciences, Ansari Nagar, New Delhi, India
style="font-style: italic; color: rgb(153, 0, 0);">


Multidrug-resistant
strains of Mycobacterium tuberculosis seriously threaten tuberculosis
(TB) control and prevention efforts. Molecular studies of the mechanism
of action of antitubercular drugs have elucidated the genetic basis of
drug resistance in M. tuberculosis. Drug resistance in M. tuberculosis
is attributed primarily to the accumulation of mutations in the drug
target genes; these mutations lead either to an altered target (e.g.,
RNA polymerase and catalase-peroxidase in rifampicin and isoniazid
resistance, respectively) or to a change in titration of the drug
(e.g., InhA in isoniazid resistance). Development of specific
mechanism–based inhibitors and techniques to rapidly detect
multidrug
resistance will require further studies addressing the drug and
drug-target interaction.


Understanding the molecular basis of drug resistance can help us
redesign old drugs, develop new drugs, and figure out how to combine
two or more drugs for a greater effect.  By increasing the
rate of
development of new strategies, it might be possible for us to keep pace
with the evolution of the bacteria.  This is an example of the
problem-solving strategy of first understanding why the problem exists,
before trying to solve the problem. 

Ok, so much for linear thinking.  Sometimes, luck turns out to
be
what does the trick. 

Paroxetine (Paxil) is a chemical, called a selective serotonin reuptake
inhibitor,  that is used as an antidepressant.  It
slows down
the action of a protein on certain nerve cells.  The protein
it
acts on is the serotonin transporter.  Wouldn’t it be really
strange if a drug that is used to treat a mental illness turned out to
be useful for treating an infectious disease?

face="Helvetica, Arial, sans-serif"> href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=13678830"
style="font-style: italic; color: rgb(153, 0, 0);">Phenylpiperidine
selective serotonin reuptake inhibitors interfere with multidrug efflux
pump activity in Staphylococcus aureus. style="font-style: italic; color: rgb(153, 0, 0);">
Int
J
Antimicrob Agents. 2003 Sep;22(3):254-61.
style="font-style: italic; color: rgb(153, 0, 0);">


Kaatz
GW, Moudgal
VV, Seo SM, Hansen JB, Kristiansen JE.
style="font-style: italic; color: rgb(153, 0, 0);">


Division
of Infectious Diseases, The John D. Dingell Department of Veterans
Affairs Medical Center and the Department of Internal Medicine, Wayne
State University School of Medicine, B4333, 4646 John R, Detroit, MI
48201, USA. gkaatz@juno.com
style="font-style: italic; color: rgb(153, 0, 0);">


Structural
variants of
phenylpiperidine selective serotonin reuptake inhibitors (P-SSRIs)
inhibited the function of two unique Staphylococcus aureus multidrug
efflux pumps. The most active compound was the paroxetine isomer NNC
20-7052, which had an IC(50) for ethidium, acriflavine, and pyronin Y
efflux of 9, 53, and 18% of its MIC, respectively, against the NorA
pump. The unbalanced effect of NNC 20-7052 on the efflux of different
substrates suggests the possibility that P-SSRIs function by a physical
interaction with NorA. Under the conditions employed pump inhibition
partially extended to the resistance-nodulation division (RND) pump
AcrAB-TolC, but not to the Pseudomonas aeruginosa RND pumps MexAB-OprM
or MexCD-OprJ.

What does this mean?  Just as human nerve cells have proteins
that
move serotonin across the cell membrane, bacteria have proteins that
move antibiotics across the cell membrane.  In the case of
bacteria, the pump only goes one way: it removes antibiotics from the
inside of the cell, rendering them useless.  These proteins
are
called efflux pumps.  And it turns out that the efflux pumps
can
be affected by the same kinds of chemicals that affect serotonin
transporters.
 

style="color: rgb(153, 0, 0); font-style: italic; margin-left: 40px;"> face="Helvetica, Arial, sans-serif"> href="http://www.biomedcentral.com/news/20030509/01">High-resolution
structures of a multidrug efflux
transporter responsible for bacterial resistance. | href="mailto:rinaldi@unica.it">By Andrea Rinaldi

style="color: rgb(153, 0, 0); font-style: italic; margin-left: 40px;"> face="Helvetica, Arial, sans-serif">Bacterial
resistance to multiple antibiotics and other drugs is a
major, increasingly common problem throughout the world. Resistance is
often associated with the overproduction of bacterial inner membrane
proteins that are capable of extruding a variety of structurally
unrelated drugs, antibiotics, and toxic compounds. In the May 9 href="http://www.sciencemag.org" target="_blank">Science,
Edward
Yu and colleagues at the target="_blank">University of California,
Berkeley, disclose the
structural basis of the activity of href="http://corpus-callosum.blogspot.com/2004/03/%09%09%09%09%09%09/pubmed/11321576"
target="_blank">AcrAB, a
constitutively expressed, major multidrug efflux system of Escherichia
coli energized by proton motive force (Science, 300:976-980,
May 9, 2003).

Now,
it turns out that the mutations that cause antibiotic resistance
in TB are not mutations that alter the structure of efflux
pumps. 
Using a linear problem-solving approach, the tendency would be to focus
on the structures that mutate in order to produce drug
resistance.  Now, at this point, there is no evidence that
paroxetine actually has any clinical utility in the treatment of
TB.  Do not rush out and get Paxil if you have TB. 
However,
the serendipitous finding that paroxetine can slow down the action of
the efflux pumps could lead to a new class of drugs that, by
themselves, do not kill bacteria; but which, in combination with
traditional antibiotics, could render them more effective. 

In the title, I said that the world is full of surprises.  It
turns out that the very first drug known to have antidepressant
properties was iproniazid.  Iproniazid happens to be an old
antibiotic that was used to treat… tuberculosis!

Comments

  1. #1 Tara C. Smith
    June 15, 2007

    Interesting article! Though I have to argue…

    Compared to something like rheumatoid arthritis, most infectious disease are simple.

    I’d suggest that infectious diseases are actually more difficult, since you have to understand both the host and the microbe (and environment plays a role as well)–for rheumatoid arthritis, you eliminate one member of that triad. (Unless, of course, it has an infectious etiology or trigger…)

  2. #2 Joseph j7uy5
    June 15, 2007

    The thing about autoimmune diseases is that each case is different. While they appear the same, or similar externally, different cases involve a different set of antigens and antibodies.

    One could argue endlessly about which branch of medicine has the most complicated disorders to treat. In retrospect I think maybe I should not have made that point, since it is really impossible to support.

  3. #3 Caledonian
    June 16, 2007

    Wouldn’t it be really strange if a drug that is used to treat a mental illness turned out to be useful for treating an infectious disease?

    The original causation was actually the other way around. It was by noting the inappropriate elatedness of TB patients in sanitariums that the first antidepressents were identified.

The site is currently under maintenance and will be back shortly. New comments have been disabled during this time, please check back soon.