New molecule may help fight superbugs

Scientists have developed a molecule that can inhibit the gene expression - believed to have originated in India - that makes bacteria resistant to antibiotics.
Scientists, including those from the Oregon State University in the US showed that the molecule's ability to inhibit expression of an enzyme that makes bacteria resistant to a wide range of penicillins.
The molecule is a peptide-conjugated phosphorodiamidate morpholino oligomer (PPMO). The enzyme it combats is known as New Delhi metallo-beta-lactamase (NDM-1), first identified in a Swedish national who fell ill with an antibiotic-resistant bacterial infection that he acquired in India.
"We are targeting a resistance mechanism that is shared by a whole bunch of pathogens," said Bruce Geller, professor at OSU.

"It is the same gene in different types of bacteria, so you only have to have one PPMO that is effective for all of them, which is different than other PPMOs that are genus specific," said Geller.
The study showed that in vitro the new PPMO restored the ability of an antibiotic - in this case meropenem, an ultra-broad-spectrum drug of the carbapenem class - to fight three different genera of bacteria that express NDM-1.

The research also demonstrated that a combination of the PPMO and meropenem was effective in treating mice infected with a pathogenic strain of E coli that is NDM-1 positive.

Geller said the PPMO will likely be ready for testing in humans in about three years.
"We have lost the ability to use many of our mainstream antibiotics," said Geller.
"Everything is resistant to them now. That is 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," Geller added.
"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 are resistant to the new, chemically modified antibiotic," he said.

That progression made the carbapenems, the most advanced penicillin-type antibiotic, the last line of defense against bacterial infection.
"The significance of NDM-1 is that it is destroys carbapenems, so doctors have had to pull out an antibiotic, colistin, that had not been used in decades because it is toxic to the kidneys," Geller said.
"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," he said.
"However, 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," Geller added.

The study was published in the Journal of Antimicrobial Chemotherapy.