Fungal compound makes superbugs susceptible to conventional antibiotic defence
Researchers at McMaster University in Hamilton have discovered a way
to disarm one of the most frightening weapons bacteria have developed to
resist antibiotic drugs. And they
discovered this potentially lifesaving compound in an unlikely place: a
soil sample from a national park in Nova Scotia. The discovery is featured today on the cover of the prestigious journal Nature.
"Our finding offers the first hope that we might be able to get around
this resistance mechanism," said Prof. Gerry Wright, who led the
research.
The discovery targets
antibiotic-resistant "superbugs," which produce an enzyme called NDM-1
(New Delhi metallo-beta-lactamase), allowing them to fight off almost
every antibiotic in the medicine cabinet, including carbepenems — an
important class of drugs that doctors keep in reserve as a last resort
against multi-resistant bacteria. The
emergence of NDM-1 in pathogens such as E. coli has turned formerly
treatable infections into potentially deadly diseases. The only weapons
left on the shelf are highly toxic with extreme side-effects, and
doctors predict the bugs will soon develop resistance even to those
drugs.
"It’s an antibiotic resistance
enzyme that we didn’t really know about until about five years ago. It
has spread around the world and multiple organisms have acquired it, and
so it’s become a pretty significant public health threat in a very
short period of time," Wright said.
"NDM-1
is the pinnacle of antibiotic resistance," said Dr. John Conly, director
of the Centre for Antimicrobial Resistance at the University of
Calgary. NDM-1 has spread to every continent except Antarctica, and
there have been NDM-1 outbreaks in Canada, including in B.C.’s Fraser
Valley.
With so much concern in the
medical community, Wright went looking for something that could tackle
NDM-1. What he found was sitting in a refrigerator in his laboratory.
That’s where he keeps his collection of soil bacteria, harvested from
random samples of Canadian dirt that he has asked students and friends
to collect as they travel around the country.
Those bacteria produce hundreds of chemical compounds, which they use
to defend themselves against other bacteria — chemicals that might
ultimately become the basis of future drugs for humans.
"We screened that collection for molecules that would reverse this
resistance, that would block this NDM-1 protein," Wright said, "and lo
and behold, we found one."
The compound they
discovered is produced by the Aspergillus fungus. It was harvested from
a forest soil sample collected by one of Wright’s students who was
hiking in Kejimkuijik National Park near Caledonia, N.S.
The molecule is called AMA (aspergillomarasmine A). Once it was
isolated, the researchers checked the chemical structure on a computer
database and realized they had rediscovered a long-discarded compound,
first identified in the 1960s as a cause of leaf wilt in plants.
"It had been catalogued," Wright said, "and then no one ever thought
of it again as being useful until we repurified it one more time 50
years later."
AMA works not by killing the
bacteria, but by turning off the resistance mechanism, making the
bacteria vulnerable to an existing drug again.
The goal is to develop AMA into a compound that could be used along
with older antibiotics, a combination approach that, if it works in
humans, could reverse antibiotic resistance, and breathe new life into
the antibiotic arsenal.
"The drugs that we
have are fantastic. We’ve used them for years, we know how to treat
patients with them. Clinicians are familiar with their side-effects,
they’re familiar with how to dose them," Wright said. "If we can stop
the resistance, then we get to use the drugs again."
The World Health Organization has called antibiotic resistance an
international public health threat. In April, it warned that the world
is headed for a post-antibiotic era where common infections and minor
injuries could become fatal if bacteria can fight off all of the
existing drugs. Already, Canadian doctors report that up to 25 per cent
of formerly routine urinary tract infections are resistant to common
antibiotics.
As resistance grows, the supply
of new drugs dwindles. Many of the large pharmaceutical companies have
gotten out of the antibiotics business, partly because the challenges in
finding effective new compounds, along with regulatory hurdles, mean
the antibiotic business is no longer profitable.
All of that means there are few new antibiotics in the drug
development pipeline. That’s why researchers are now exploring the idea
of using a combination approach to disarm resistant bacteria and make
them vulnerable to the old drugs.
"We need
to look at synergistic ways to attack bacteria, rather than one drug,"
said Dr. David Patrick, medical epidemiology lead for antimicrobial
resistance at the B.C. Centre for Disease Control. "It’s a wonderful
discovery, if it can bridge the gap from test tube to people."
"This may rank as a very significant discovery, provided this agent is non-toxic in humans," said Conly.
So far, the McMaster researchers have shown that the compound is
effective against bacteria carrying NDM-1. They’ve also shown that it
fights infection in mice and rats.
0 comments:
Post a Comment