For the past 100 years, antimicrobials like penicillin have been a key pillar of public health systems, turning once dangerous infections into curable conditions. Used to prevent post-operative infections, treat sepsis, and keep people alive throughout routine cancer care, they have been touted as adding 20 years onto global life expectancy.

It’s no wonder, then, that the World Health Organization lists antimicrobial resistance (AMR) among the top ten global public health threats facing humanity. Already, many antibiotics are losing efficacy, and this grim trend shows no sign of abating.

In 2018, half a million people suffered from multi-drug resistant tuberculosis, which could not be treated with the two most powerful medications. Drug-resistant malaria may not be far behind. By 2050, AMR could contribute to ten million deaths every year, with lower-income countries paying the heaviest price.

Clearly, the over-prescription of antibiotics will have to stop if we want to make headway in addressing AMR. In the US alone, doctors write 47 million unnecessary antibiotic prescriptions every year – and that is not to mention their overuse in farm animals, which constitutes around 80% of total usage in some countries.

This is only one piece of the puzzle, however, and there is also work to be done in terms of infection surveillance, prevention and diagnostics.

There is also a pressing need for new therapies that can work as alternatives to antibiotics. While new antibiotics are being developed, the pipeline is generally considered to be weak – with the majority showing only limited benefits when compared to existing antimicrobials.

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Researchers, then, are thinking bigger and attempting to develop entirely new strategies for treating infectious disease.

Biological antibiotics

Dr Natalia Freund has found one potential solution in the form of a ‘biological antibiotic’. Together with her team at Tel Aviv University, and two laboratories in the US and China, she was able to isolate monoclonal antibodies from a patient with active tuberculosis. When delivered to laboratory mice, these antibodies were able to hinder the growth of tuberculosis bacteria in a similar manner to an antibiotic.

“Antibiotics are highly efficacious and cost-effective, and therefore for the last years have been our only weapon against bacterial infections,” said Freund.

“Unfortunately, antibiotics become less and less effective, and in the main cases of drug-resistance physicians are empty handed in finding an appropriate treatment for their patients. Therefore, new ways to kill bacteria are urgently needed.”

Her team’s study, published in Nature in January, is an initial proof of concept demonstrating that monoclonal antibodies might be suitable for this purpose.

Focusing on a particular protein on the tuberculosis bacillus cell wall, the researchers found two antibodies that blocked its action. Since the protein in question (a phosphate pump) is common to all strains of TB, the antibodies should in theory be effective against drug-resistant versions of the disease.

“The model that has proven successful in this study will enable us to extend our future work to include other diseases such as pneumonia and staphylococcus infections,” added Freund.

Storming bacterial cities

Another strategy might be to target bacterial groups known as biofilms. Sometimes dubbed ‘cities for microbes’, biofilms are dense structures of bacteria, living in coordinated communities and protected by a layer of slime.

This is an adaptive strategy for the bacteria, which become up to 1,000 times more resistant to antibiotics as a result of their city-like fortifications. According to the National Institutes of Health, 65% of all microbial infections are associated with microbes growing this way.

A number of researchers have reasoned that if you were to disperse the biofilm, you could render the bacteria more susceptible to antibiotics. Dr Karin Sauer at Binghamton University has found that exposing bacterial communities to pyruvate-depleting conditions (taking away a substance that enables them to survive without oxygen) can break down a biofilm.

Another team of researchers in Belgium and Oxford are working on ways to ‘inhibit the social traits’ of bacteria, so as to stunt their growth and survival in biofilms. They used an extracellular polymeric substance (EPS) inhibitor to prevent EPS formation.

Because EPS (the slime-like substance that protects the microbes) is a ‘public good’, shared by all the bacteria, resistant strains of bacteria are unlikely to emerge – after all, it would be costly for them to produce this ‘public good’ by themselves.

This gives rise to the intriguing idea, derived from social evolution theory, that ‘public good inhibition’ might combat the rise of AMR. To go back to the city analogy, this is less about storming its walls and more about manipulating its politics.

Enhancing the body’s immune response

Professor David Dockrell’s team at Edinburgh University (along with colleagues in Sheffield, Newcastle and Birmingham) hope to find ways to clear bacterial infections by enhancing the body’s natural immune response. By understanding the mechanisms that enable most people to fend off bacteria, they can learn how to re-engage this system when it fails.

“The basic principle is that many infections come about because of bacteria that we often carry in our body, and the first part of our body’s defence against those organisms has failed,” he says.

“For most people, the response works very well, but a small percentage of people become sick. Our idea is we can recalibrate some of those responses, so they work more like how they do in the people who don’t become sick.”

The researchers demonstrated that a structure in the macrophage (an immune cell that ‘eats’ bacteria) releases substances called mitochondrial reactive oxygen species (mROS), which are necessary to kill the bacteria. Through repurposing medications that are currently used for other indications, they have been able to enhance bacterial killing via mROS.

“We’re also trying to identify new mechanisms to identify how the bacteria are killed, and we’ve developed a pipeline of tests to validate our findings,” says Dockrell. “We’re trying to use this information to identify new targets for treatments.”

These treatments, he thinks, could curb how much we use antimicrobials further down the line.

“It may be that some of our findings could be used as preventative strategies, or they could be combined with antimicrobials to limit our reliance on antimicrobials,” he says. “Obviously if we do that, we can slow down the emergence of AMR resistance.

“The approaches we’re using can be applied to both human populations and animals, so clearly they can have pretty wide traction. The other thing they can do is to help us predict who’s at risk of infection, so we can reserve the treatments we have more selectively for the people who really need them.”

While it may be some time before innovations of this kind hit the clinic, they do give grounds for hope that AMR may not be the looming catastrophe many fear.