New molecule knocks out superbugs' immunity to antibiotics

Michael Irving

January 20th, 2017

In the fight against superbugs, a newly-developed molecule may allow us to use existing antibiotics again(Credit: lightsource/Depositphotos)One of the most terrifyingly-plausible doomsday scenarios is the rise of superbugs, strains of bacteria that are evolving a resistance to our most powerful antibiotics. To try to prevent that situation occurring, scientists are building a creative array of weapons by developing new materials, gels, lights and molecules to fight antibiotic-resistant bugs, and even pitting bacteria against each other. Now researchers have created a new molecule that can make previously antibiotic-resistant bacteria vulnerable to existing drugs again.Last year, a report commissioned by the UK government outlined a grim possible future that could "cast us back into the dark ages of medicine," where our drugs simply don't work and rampant antibiotic-resistant bacteria are responsible for up to 10 million deaths per year. That report predicted those horrors for the year 2050, but unfortunately, the killer bugs might be ahead of schedule: our last line of defense against bacteria, a class of antibiotics called carbapenems, are already beginning to fail in large numbers.
"We've lost the ability to use many of our mainstream antibiotics," says Bruce Geller, one of the study's authors. "Everything's resistant to them now. That's left us to try to develop new drugs to stay one step ahead of the bacteria, but the more we look the more we don't find anything new. So that's left us with making modifications to existing antibiotics, but as soon as you make a chemical change, the bugs mutate and now they're resistant to the new, chemically modified antibiotic."
Some of the most devastating bacteria get their antibiotic resistance by producing an enzyme known as New Delhi Metallo-beta-lactamase (NDM-1). It's this enzyme that the new research is targeting, by developing a molecule called a peptide-conjugated phosphorodiamidate morpholino oligomer (PPMO). This inhibits the bacteria's expression of NDM-1, essentially destroying its antibiotic resistance and allowing existing drugs to be effective once again.
"The significance of NDM-1 is that it is destroys carbapenems, so doctors have had to pull out an antibiotic, colistin, that hadn't been used in decades because it's toxic to the kidneys," Geller explains. "That is literally the last antibiotic that can be used on an NDM-1-expressing organism, and we now have bacteria that are completely resistant to all known antibiotics. But a PPMO can restore susceptibility to antibiotics that have already been approved, so we can get a PPMO approved and then go back and use these antibiotics that had become useless."
The study combined the new PPMO with meropenem, a type of carbapenem antibiotic that's effective against a broad range of bugs, and pitted it against three different types of bacteria that make use of NDM-1. In all cases, the PPMO restored meropenem's ability to kill the bacteria in vitro, and also managed to kill off an NDM-1-expressing strain of E. coli in tests in mice.
"We're targeting a resistance mechanism that's shared by a whole bunch of pathogens," says Geller. "It's the same gene in different types of bacteria, so you only have to have one PPMO that's effective for all of them, which is different than other PPMOs that are genus specific."
Geller says the new drug should be ready for human testing in about three years. The research was published in the Journal of Antimicrobial Chemotherapy.
Source: Oregon State University

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