Were you to read about a criminal who acquired superman-like powers, you could imagine how the story would unfold. The criminal would wreak mayhem, and the authorities would fail to subdue him, despite unleashing conventional weapons of escalating power. Then, it would occur to someone to deploy an unconventional weapon—kryptonite, or something like it—robbing the criminal of his superpowers and finally subduing him.
In broad outline, this scenario applies to a certain kind of superbug—carbapenem-resistant Gram-negative pathogens. By acquiring metallo-β-lactamases (MBLs) such as New Delhi metallo-β-lactamase-1 (NDM-1), ordinary bugs become resistant to penicillin, cephalosporin, and carbapenem antibiotics. According to the World Health Organization, the gene for NDM-1 gene has emerged as a global public health threat.
The rising danger posed by NDM-1 did not escape the notice of researchers at McMaster University. “It came out of nowhere. It has spread everywhere and has basically killed our last resource of antibiotics, the last pill on the shelf, used to treat serious infections,” explained Gerry Wright, director of the McMaster University’s Michael G. DeGroote Institute for Infectious Disease Research. “This is public enemy number one.”
Rather than join the struggle to develop new antibiotics against carbapenem-resistant Gram-negative pathogens, Dr. Wright and his colleagues took a different approach. They sought a different kind of weapon, and they looked for it in the natural environment. These efforts have been described in a paper that appeared June 25 in Nature, in an article entitled “Aspergillomarasmine A overcomes metallo-β-lactamase antibiotic resistance.”
The approach taken by the researchers was explained by an accompanying Nature News and Views contribution: “Most members of our current antibiotic arsenal originate from screens of naturally occurring chemicals produced by soil microorganisms. [The researchers] reasoned that replication of this approach might lead to the discovery of small molecules that could resensitize bacteria to drugs against which they have developed resistance. The authors performed a screen of naturally occurring microbial extracts to find compounds that could inhibit ... NDM-1.”
In other words, the approach was something like scouring the planet Krypton for a substance that would counter ill-gotten superpowers. The search for an antibiotic adjuvant, however, had to extend only as far as Nova Scotia. Here, soil samples contain a fungal natural product, aspergillomarasmine A (AMA).
After AMA turned up in a screen, it turned out to be a rapid and potent inhibitor of the NDM-1 enzyme and another clinically relevant MBL, VIM-2. “AMA also fully restored the activity of meropenem against Enterobacteriaceae, Acinetobacter spp., and Pseudomonas spp. possessing either VIM or NDM-type alleles,” wrote the researchers.
Dr. Wright and his team created a cell-based screening method to take the NDM-1 gene, combine it with harmless E. coli bacteria and then isolate a molecule capable of stopping NDM-1 in its tracks.
NMD-1 requires zinc to thrive but finding a way to remove zinc from it without causing a toxic effect in humans was a daunting task, until the discovery of the fungal molecule, which appears to perform the job naturally and harmlessly.
Scientists then tested the theory on mice infected with an NDM-1 expressing superbug. The mice that received a combination of the AMA molecule and a carbapenem antibiotic survived, while those that received either an antibiotic or AMA alone to fight the infection did not survive.
“This will solve one aspect of a daunting problem. AMA rescues the activity of carbapenem antibiotics, so instead of having no antibiotics, there will be some,” said Dr. Wright.