Soil bug compound foils antibiotic resistance

By Helen Branswell
The Canadian Press

TORONTO – A soil sample from Nova Scotia has yielded a compound that could help fight antibiotic resistance. Researchers from McMaster University in Hamilton have discovered that a fungus found in the sample produces a chemical that inactivates the dangerous NDM-1 resistance gene, making bacteria containing it vulnerable to the antibiotics NDM-1 normally helps them evade.

The scientists liken the compound to an adjuvant, a chemical that enhances the power of vaccines.

“Simply put, the molecule knocks out NDM-1 so the antibiotics can do their job,” said Gerry Wright, the biochemistry professor who leads the team which conducted the research.

Their finding was published Wednesday in the scientific journal Nature.

The precursor chemicals that antibiotics are based on exist in nature and are often found in soil. For years, pharmaceutical companies searching for new versions of these important drugs maintained libraries of bacteria and fungi found in soil, testing the chemicals they produced to see if they had could be used to fight infections. But as new finds dwindled companies have largely withdrawn from this field, leaving little in the antibiotic pipeline.

With the rise in antibiotic resistance and the emergence of multi-drug resistance factors like NDM-1, which confers resistance to almost all existing antibiotics, experts have warned the world is facing a future in which antibiotics no longer work. That could mean surgeries and procedures we view as standards of modern medicine would be too dangerous to undertake because of the risk of infection.

Wright figured that if soil has been a source of antibiotics, it might also contain small molecules that might counteract resistance when taken in combination with antibiotics. So he and his team began to compile their own library from soil samples taken from across Canada. It now contains about 10,000 samples.

“If we accept that finding things that just kill bacteria outright is going to be hard to find, then why don’t we try things that incapacitate resistance? And those same collections should be great sources of inhibitors of resistance,” he explained in an interview.

“People in my lab, whenever they were on vacation, I just told them to take a couple of teaspoons of soil from wherever they were…. In a teaspoon of soil, there are probably a billion bacteria.”

The researchers grew up the microbes found in the soil samples, extracting the compounds those bacteria and fungi produce. They then began to add them to dishes containing an antibiotic and E coli bacteria were resistant to the drug because they had been engineered to contain the NDM-1 gene. If the combination did not kill the bacteria, the compound added nothing.

In fewer than 1,000 tries — a small number for this type of work, Wright says — they found a compound that did knock out the NDM-1 gene’s powers. It was a molecule called aspergillomarasmine A — AMA for short — which is produced by a fungus called Aspergillus versicolor.

To confirm the finding, they tested the antibiotic and AMA combination on 229 strains of resistant bacteria isolated from patients around the world over the past decade. The combination was effective at restoring antibiotic susceptibility in 88 per cent of these strains.

To test it further, the McMaster team infected mice with what should have been a lethal dose of Klebsiella pneumoniae that contained the NDM-1 gene. More than 95 per cent survived the experimental infection.

But mice are not men and much testing remains to be done to see if this compound could be used safely and successfully in people.

“The next stage for us is to do the sort of hard slog — toxicology and pharmacology studies to make sure we’re not seeing any changes in physiology that might send this compound into the dust bin. So far the experiments are positive. But they could all turn in a second,” Wright admitted.

“I have no idea whether or not this will actually have legs in the clinic or not, but we’re certainly marching towards that direction.”

A commentary on the finding suggested it is hopeful, but warned there could be hurdles on the road to use in people.

For one thing, it noted AMA has previously been shown to inhibit angiotensin-converting enzyme (ACE), which is naturally produced by humans. It causes blood vessel constriction and increases blood pressure. People with high blood pressure are often prescribed ACE-inhibitor drugs.

The authors of the commentary, Djalal Meziane-Cherif and Patrice Courvalin from the Institut Pasteur in Paris, said it remains to be seen if AMA would trigger serious side-effects in people, though they noted that was not the case in mice.

They also warned that resistance to the combination could arise — something Wright accepts as a fact of life.

“The organisms are going to keep evolving different ways to get around them (antibiotics) and they’re going to collect these (resistance) genes in multiple packages. So maybe in the future we’ll be looking at cocktails of three compounds, four compounds,” he said.

“That’s common … in HIV, it’s common in oncology, it’s common in tuberculosis treatment. It’s just not common in treating infection…. It just might be in the future.”