PA-824 Is a
Promising New
Anti-TB Drug
Scientists
from the National
Institute of
Allergy and
Infectious Diseases
(NIAID), part
of the National
Institutes of
Health, have
determined how
a promising
drug candidate
attacks the
bacterium that
causes tuberculosis
(TB). Published
in Proceedings
of the National
Academy of Sciences,
the finding
may help scientists
optimize the
drug candidate,
PA-824, which
targets Mycobacterium
tuberculosis
(M.
tb).
“PA-824,
now in early
stage clinical
trials, holds
promise for
shortening the
TB treatment
regimen, which
is currently
cumbersome and
lengthy,” says
NIAID Director
Anthony S. Fauci,
M.D. “This new
finding will
allow a streamlined
approach for
making improved
versions of
the drug.”
“Previously,
we were flying
blind in trying
to optimize
PA-824 in a
rational way
because we didn’t
know which M.
tb
protein was
the target of
PA-824’s action,”
says NIAID scientist
Clifton Barry,
III, Ph.D.,
who headed the
research team.
In
preclinical
testing, PA-824
showed evidence
of being effective
against both
actively dividing
and slow-growing
M.
tb,
giving rise
to optimism
that the compound
may be useful
in treating
both active
and latent TB.
(For information
about the first
clinical trial
of PA-824, see
June
14, 2005, NIAID
press release.)
PA-824
must be chemically
activated in
the bacterium
before it exerts
its anti-tubercular
effect, notes
Dr. Barry. Earlier
research had
sketched out
the first few
steps in this
process, but
Dr. Barry and
his colleagues
wanted to pinpoint
the precise
protein that
binds PA-824
and transforms
it into a lethal
molecule for
TB.
The scientists
approached the
problem indirectly
by searching
for M.
tb
mutants that
resisted the
killing power
of PA-824. The
team confirmed
previous research
suggesting that
resistance usually
occurs when
M.
tb
lacks components
called FGD1
and F420, neither
of which interacts
directly with
the drug.
Next, the
investigators
screened for
PA-824-resistant
M.
tb
that retained
sensitivity
to a close relative
of PA-824. Within
this subgroup
of PA-824-resistant
bacteria, the
team identified
those mutant
strains with
FGD1 and F420.
The investigators
reasoned that
resistance to
PA-824 in mutants
possessing FGD1
and F420 must
be due to a
mutation in
the M.
tb
protein that
directly interacts
with PA-824.
But determining
exactly which
of M.
tb’s
thousands of
proteins was
changed in these
mutants proved
difficult, says
Dr. Barry. Conventional
genetic techniques
for comparing
normal and mutant
strains of M.
tb
failed, so the
team turned
to a specially
modified microarray-based
technique, called
comparative
genome sequencing,
developed by
NimbleGen Systems,
Inc. (Madison,
WI).
This was the
first time the
technique has
been used to
identify a protein
involved in
TB drug resistance,
notes Dr. Barry.
Using the
NimbleGen technique,
which effectively
re-sequences
the entire genome
of the bacterium,
the scientists
quickly pinpointed
the protein
altered in the
PA-824-resistant
mutant strains
of M.
tb.
In the past,
such a complete
genome comparison
might have taken
many months
of work; this
new technology
enables scientists
to zero in on
the specific
genetic difference
between mutant
and normal bacterial
strains in just
days, says Dr.
Barry.
The scientists
found a total
of four PA-824-resistant
mutant strains:
two lacked the
newly described
M.
tb
protein altogether,
while the remaining
two mutants
evidently acquired
resistance to
PA-824 through
a mutation that
made the protein
unable to bind
to the drug,
Dr. Barry says.
With the
discovery of
the specific
protein that
interacts with
PA-824, Dr.
Barry and colleagues,
including researchers
at the Novartis
Institute for
Tropical Diseases
in Singapore,
have information
they can use
to produce improved
PA-824 relatives
and accelerate
the pace of
new TB drug
development.
03/28/06
Reference
UH Manjunatha
et
al.
Identification
of a nitroimidazo-oxazine-specific
protein involved
in PA-824 resistance
in Mycobacterium
tuberculosis.
Proceedings
of the National
Academy
of Sciences
(2005) DOI:
10.1073/pnas.0508392102.
