A new antibiotic for
drug-resistant tuberculosis
TUBERCULOSIS has
plagued humanity for thousands of years. The discovery in the 19th
century of its cause,
a bacterium (pictured above) called Mycobacterium tuberculosis, and the
consequent
development of better hygiene, helped bring that plague under control. Then, in
the mid-20th century,
what many hoped would be the final nail in its coffin appeared:
antibiotic drugs.
Unfortunately, TB is
back. After a few decades in which antibiotics did indeed seem to be
working miracles,
some strains of M. tuberculosis have evolved resistance to them. In 2015
5% of the world’s 10m
cases failed to respond to treatment with isoniazid and rifampicin, the
drugs of first
resort. Half of those non-responders were infected by strains of the bacterium
immune to second-line
treatments as well. Most microbiologists regard these numbers as
portents of worse to
come. That is driving a search for new antibiotics against which M.
tuberculosis has
evolved no resistance.
Eshwar
Mahenthiralingam of Cardiff University and Greg Challis of the University of
Warwick, both in
Britain, think they have found one. As they and their colleagues describe in
the Journal of the
American Chemical Society, they have discovered a compound, produced
by another bacterial
pathogen, that kills resistant strains of M. tuberculosis.
This compound, which
they call gladiolin, is created by Burkholderia gladioli—a bacterium,
generally rare, that
thrives in the lungs of those suffering from cystic fibrosis. It is able to
gain a foothold there
because the respiratory tracts of such patients are clogged with mucus
that inhibits the
actions of immune-system cells which would otherwise destroy the invaders.
What interested Dr
Mahenthiralingam and Dr Challis about B. gladioli was that, once
established in a
patient’s lungs, it seems able to keep rival bacteria such as M. tuberculosis
at
bay. This suggests it
is engaging in chemical warfare.
To isolate the agent
that inhibits B. gladioli’s competitors, the researchers cultivated samples
from a patient with
cystic fibrosis and analysed the chemicals secreted by bacteria therein. It
was thus they
discovered gladiolin, which shuts down bacterial versions of the gene for an
enzyme called RNA
polymerase that is crucial for life.
This was interesting.
But it was also reminiscent of a false dawn involving another substance,
etnangien, which was
discovered in 2007 and which also inhibits RNA polymerase.
Unfortunately,
etnangien proved chemically unstable and thus impossible to use as a drug.
The first task Dr
Mahenthiralingam and Dr Challis undertook was therefore a detailed
comparison of the
two. They established that the parts of etnangien molecules which cause
their instability are
not shared by gladiolin. That suggested gladiolin might indeed be robust
enough for use
against tuberculosis, and encouraged them to test it further.
The new substance
performed reasonably well against a strain of tuberculosis that had no
resistance to
antibiotics. A solution of 400 nanograms (billionths of a gram) per millilitre
was
enough to inhibit the
growth of such bacteria. But isoniazid and rifampicin performed better.
They needed only 40
nanograms and 1 nanogram per millilitre of solution respectively to
keep the
non-resistant bugs under control. Where gladiolin did shine, though, was
against a
strain of
tuberculosis known for its resistance to isoniazid and rifampicin. Even 10,000
nanograms per
millilitre of either of those two drugs was insufficient to harm it. However, a
mere 1,700 nanograms
per millilitre of gladiolin proved enough to knock it out.
Whether gladiolin can
be taken out of the Petri dish and made into a useful drug will require
many clinical trials
to discover. But, in a world crying out for new antibiotics, it seems a
useful lead.
Source: The Indian Express
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