New metal-based antibiotic tears up bacteria

08 June 2019

BACTERIA

Artists impression of bacteria

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A new ruthenium-based antibiotic that destroys resistant bacteria has been developed by researchers in the UK...

Bacteria are evolving resistance to our antibiotic arsenal at an alarming rate. This looming "antibiotic apocalypse", when no agents remain that are effective, threatens to render some routine surgical procedures impossible, and could see us falling victim to infections we currently regard as trivial. Even today, an average of 29,000 U.S and 25,000 EU citizens die each year as a result of microbial resistance, with an estimated 10 million deaths in 2050.

One of the factors underpinning the rise of superbugs is that, apart from changing the structures of their surfaces to makes themselves more resilient, these bacteria have evolved other effective methods to rid themselves of antibiotics. “They can develop channels along their membranes called 'efflux pumps', which pump out the antibiotic,” explains Sheffield University's Kirsty Smitten, a member of the team behind the new antibiotic agent that can target both Gram positive and Gram negative bacteria.

This distinction matters. "Gram-positive bacteria have one cell membrane and then a cell wall, whereas gram-negative bacteria have an inner membrane, the cell wall, and then an outer membrane." It is this more complex arrangement of the bacterial cell wall in Gram negative bacteria, which cause pneumonias, urinary tract infection, and bloodstream infections, that makes these bacteria trickier to hit with antibiotic agents.

And despite the massive projected costs of antibiotic resistance, few significant advances have been made in the field over the past 50 years. That is, until Smitten’s ruthenium-based compound was shown not only to be able to penetrate the extra defensive layer of the Gram-negative bacteria, but get inside the bacterial cells themselves.

A microscopy technique enabled the team to follow what happened when the new compound was added to drug-resistant E.coli bacteria in a dish. The ruthenium compound caused the membranes of the bacterial cells to peel off in layers, destroying the cells. The agent also appears to knock out the bacterial efflux pumps, helping the drug to concentrate in the cell and ensure complete destruction.

Equally importantly, initial tests on animal cells show that the compound is selective for bacteria and does not damage non-bacterial cells; it is also active at concentrations that could readily be achieved in the body.

But won't the bacteria simply become resistant to the new compound, like they have to most of the other antibiotic classes we have invented? Smitten and her team don’t believe so. Bacteria are able to produce an enzyme that attacks a component of the chemical structure common to penicillin-like antibiotics. The compound tested by Smitten and her team does not rely on the same structure, meaning the bacteria are not able to break down the compound in the same way.

Of course, time will tell. For now the next steps are safety and efficacy tests in animals, followed by human clinical trials. What is certain is that the results cannot come soon enough...

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