Bug-Born Breakthrough

According to a recently published report by the World Health Organization (WHO, see box), levels of resistance to antibiotics are on the rise. And there’s no sign of this trend reversing – on the contrary: each year, more than a million people around the world die from bacterial infections that can no longer be treated with antibiotics. So-called gram-negative bacteria in particular, which cause life-threatening diseases such as sepsis and pneumonia, are becoming more and more difficult to combat.

That’s why scientists around the world are looking for new active substances to tackle these pathogens. “But the pipeline of new drugs is alarmingly empty,” says professor of chemistry Oliver Zerbe. He’s devoted the last nine years of his research to the quest of finding new antibiotics. “It’s vital not just to improve existing antibiotics, but to find entirely new classes of active substances to which there’s currently no resistance,” says Zerbe.

The World Health Organization (WHO) recently published its latest report on antibiotic resistance. According to the latest figures, among the world’s most common infections, one in six bacterial pathogens was resistant to antibiotics in 2023. Between 2018 and 2023, antibiotic resistance increased in over 40 percent of the applications monitored by the WHO. Gram-negative bacterial pathogens pose the greatest threat. These include Escherichia coli and Klebsiella pneumoniae, which lead to the most serious bacterial infections that are often associated with sepsis, organ failure and death.

Around the world, more than 40 percent of the strains of Escherichia coli and over 55 percent of the strains of Klebsiella pneumoniae are now resistant to the first-choice antibiotics used to treat these diseases. This is why alternative drugs are having to be used more frequently. However, they are expensive, more difficult to access and often unavailable in low and middle-income countries.

How can the situation be improved? According to the WHO, important steps include preventing infections, using antibiotics correctly, monitoring the consumption of antibiotics and conducting research into new drugs.

Oliver Zerbe’s research into the development of novel antibiotics is supported be the UZH Foundation.

Up until now, the primary aim of antibiotics has been to prevent the cell wall of bacteria from building up, disrupt their metabolism or damage their genetic material to kill them off. “It’s also been more than 50 years since a new point of attack against bacteria was last found,” says Zerbe. He himself is one of the pioneers on the path to finding a new class of antibiotics, known as Outer Membrane Protein Targeting Antibiotics (OMPTA).

The OMPTA approach developed at UZH targets the dreaded gram-negative bacteria. Unlike their gram-positive counterparts, they have not just one, but two membranes as an outer shell. Substances for constructing the outer membrane need to be able to circulate between the two membranes in these bacteria. OMPTA antibiotics are intended to block the bridge for this transportation, thus preventing the cells from dividing.

This innovative approach was developed by Zerbe’s predecessor, the UZH chemistry professor John Robinson. He worked with the UZH start-up Polyphor to produce a first active substance called murepavadin. It proved to be effective in clinical trials, but failed because of its side effects – it damaged the kidneys. However, murepavadin has not been abandoned entirely. A pharmaceutical company is now trying to make the active substance capable of being used as an inhalation spray. This could enable the antibiotic to reach its site of action in the lungs directly without needing to pass through the bloodstream and therefore the kidneys.

In the meantime, Oliver Zerbe is focusing on a novel OMPTA active substance called thanatin. The natural antibiotic substance is produced by stink bugs, which use it to defend themselves against bacteria. For humans, thanatin does not have a sufficiently strong antibiotic effect, is broken down too quickly in the blood and develops resistance too soon. “Nevertheless, it’s still suitable as a starting molecule for new antibiotics. But this will require targeted modifications,” explains Zerbe.

This is where the specific expertise of the chemistry professor and his team comes into play. Their area of expertise is elucidating the structure of proteins. This involves deciphering the three-dimensional structure of molecules down to the level of individual atoms. Using nuclear magnetic resonance (NMR) spectroscopy, the researchers analyzed thanatin and how it binds to a receptor between the membranes of the bacteria. By doing this, they laid the foundation to enable Polyphor and its successor start-up Spexis to chemically modify the structure of the natural substance in a targeted way, improving its properties to help in the fight against pathogenic bacteria. Incidentally, the researchers actually have the antibiotic substances produced biotechnologically by bacteria that are similar to the ones they want to fight.

The first step was to make thanatin capable of homing in on two of the most dangerous bacteria that most frequently develop levels of resistance. Preclinical trials in animal models revealed a high level of efficacy, especially against multidrug-resistant pathogens. In contrast to broad-spectrum antibiotics, thanatin also offers the advantage that it attacks only certain bacteria and preserves other bacteria, such as in our microbiome. Zerbe and his team are now working on adapting thanatin for the fight against two more gram-negative pathogens.

The aim is to develop a platform that can be used to adapt thanatin continuously to new target bacteria. The project is being supported by the Swiss National Science Foundation and the UZH Foundation. Zerbe reckons that the platform should be ready in about five years. He hopes that a pharmaceutical company will then express an interest in it and support the new class of antibiotics through the expensive clinical test phases on humans and subsequently get it market-ready – it would be the first ever OMPTA antibiotic available on the market.

“Securing the follow-up funding after the basic research has been conducted at universities is the major challenge in developing new antibiotics,” says Zerbe. The crux of the matter is that, in contrast to drugs used to treat chronic diseases, for example, antibiotics are only used for a short time and as infrequently as possible in order to minimize the development of resistance. This means they aren’t all that profitable for pharmaceutical companies.

“Innovative approaches are urgently required to create new incentives to develop antibiotics,” says the UZH professor. Although there are ideas on how to do this, few of them have yet been realized. But there are some glimmers of hope. For example, there are now funds that specifically support antibiotics research. In addition, the U.S. Food and Drug Administration (FDA) has recently started processing applications for drug approval more quickly if the pharmaceutical companies also commit to invest in antibiotics research.

“I think what’s known as the subscription model is really exciting,” says Zerbe. It’s comparable to having a fire department: municipalities and city councils also pay for this in the hope that they’ll need to deploy it as infrequently as possible. In a similar way, states could compensate pharmaceutical companies for developing antibiotics, regardless of how many drugs they’re subsequently able to sell. “It can’t be right that start-ups go under because they’re unable to raise enough money or experience a setback on the path to producing new antibiotics,” says Zerbe – also reflecting on the experience of the start-up Polyphor, which had to give up after suffering setbacks.

Time is pressing, levels of resistance are increasing. Is Oliver Zerbe confident that we’ll succeed in reversing the trend? “I think that as a researcher you always have to be confident, otherwise you’ve chosen the wrong profession,” he says. And he recounts one of his recent successes: his research group has managed to identify a second target to attack in the connection between the inner membrane and outer membrane of gram-negative bacteria. This means that in future, thanatin could block the exchange of substances at two sites at once.

To stop this from happening, two mutations would have to occur simultaneously at the corresponding sites in the bacterium, which Zerbe believes is very unlikely: “This means we can delay the development of new levels of resistance to an active substance like this for even longer.” However, it will be a few more years before this happens. And just as Zerbe took on the idea of OMPTA from his predecessor John Robinson, he too will pass the baton on to a successor when he retires in three years’ time – and will continue to share in the excitement to see whether the project succeeds.