Transcript Topic #1

CHEMISTRY 2000
Topics of Interest #1:
Blowing up Bacteria
with Nitrogen Monoxide (NO)
Current Treatments for Tuberculosis
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Mycobacterium tuberculosis, the bacteria causing tuberculosis (TB),
infects one third of the world’s population! Only about 10% of
those infected develop symptoms; the other 90% have what is
called a latent infection in which immune cells have isolated the
bacterial cells by surrounding them.
Since latent infections can easily turn into symptomatic infections, it
is still important to treat latent infections – particularly since the
survival rate for symptomatic infections is only ~50%.
TB is treated by using a mixture of antibiotics to kill the bacteria.
Due to the slow growing nature of M. tuberculosis, it is necessary
for a patient on antibiotics to take them for 6-12 months to fully
clear the infection. If they don’t, antibiotic resistance can become a
problem – and frequently does.
Development of new antibiotics is therefore important.
R. Singh, C.E. Barry et al Science (2008) 322, 1392-1395;
summarized in Nature (2008) 456, 548. Image above from CDC.
Current Treatments for Tuberculosis
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The antibiotics in the anti-TB cocktail operate via different means:
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Rifampicin interferes with protein synthesis by blocking the DNA->RNA
step of the DNA->RNA->protein sequence.
Streptomycin also interferes with protein synthesis.
Isoniazid and ethambutol interfere with production of essential
components of the bacterial cell wall. As a result, they are primarily
effective when the bacteria are dividing (and needing to build more cell
walls).
When a healthy person is infected by tuberculosis, their immune
system attempts to contain the infection by engulfing the bacteria
in cells which produce NO, a highly reactive radical which is,
according to Dr. C.E. Barry, “akin to a bomb blast that kills the
bacteria from within”. Unfortunately, the amount of NO produced
is often not enough to kill all of the bacteria.
R. Singh, C.E. Barry et al Science (2008) 322, 1392-1395;
summarized in Nature (2008) 456, 548. Image above from CDC.
Nitric Oxide and Tuberculosis
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A new antibiotic, still in the experimental stages, has been found to
be capable of killing dormant cells in the same way as the human
immune system – by releasing NO. Controlling the dose of the
antibiotic would allow control of the amount of NO released.
O
N
O2N
enzyme
in
bacteria
N
O
NO
dead
bacteria
H
experimental antibiotic PA-824
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O
CF3
After the drug enters a bacterial cell, an enzyme produced by the
bacteria itself breaks down the drug, releasing NO. This targets the
NO directly against the bacterial cell and means that the drug
should not produce NO if taken up by human cells as they lack the
relevant enzyme.
R. Singh, C.E. Barry et al Science (2008) 322, 1392-1395;
summarized in Nature (2008) 456, 548. Image above from CDC.
Nitric Oxide and Tuberculosis
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How does NO kill bacteria?
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NO has an odd number of electrons. It must therefore have at least
one unpaired electron, making it a free radical:
Particular targets for the NO free radical are enzymes containing sulfur
(very common) and/or iron (recall discussion of CO poisoning in CHEM
1000). It also scavenges any free iron in the cell.