Battling antibiotic resistance: a new protein powered solution

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The discovery of antibiotics fundamentally changed healthcare in the 20th century. Deadly infections suddenly became treatable and millions of lives were saved. But excessive antibiotic use in both healthcare and agriculture has allowed some microbes to become resistant. Resistance has even been reported to last resort treatments, like colistin, in the past few years. With classic antibiotics failing, will trivial infections become deadly again or will we manage to find new solutions? In this two-part series, we will look into some of the fundamentally different therapeutics that are being developed as alternatives to traditional antibiotics. In our first installment, we examine a Belgian innovation called Pept-ins™.

AMR can fundamentally change healthcare

The WHO considers antimicrobial resistance (AMR) one of the direst current threats to global health. The organization is calling for greater innovation and investment in the search for new medicines, vaccines and diagnostic tools. A recent study in The Lancet found that infections with antibiotic-resistant bacteria accounted for over 33 thousand deaths in Europe in 2015. This was a vast increase compared to figures from 2007. The current burden of these infections is considered similar to that of influenza, tuberculosis, and HIV combined.

“The Gram-negative bacteria pose a particular threat,” says Els Beirnaert, CEO of Aelin Therapeutics (the company developing the Pept-in™ technology for antimicrobial applications). “Routine medical procedures such as hip replacements, appendectomies or Caesarean sections always incur a risk of infection. With the rise of AMR, the impact of new antibacterial treatments is therefore not just about curing diseases; it is also about being able to keep performing these routine procedures safely.”

A fresh perspective

The scientific community has recognized the threat of AMR and the search for new antimicrobial treatments is in full force. However, most initiatives rely on screening and modifying natural compounds, similarly to how penicillins and cephalosporins were discovered decades ago. Pept-ins™, by contrast, take a fundamentally different approach to tackling the problem.

Regulatory authorities like EMEA and FDA are streamlining the approval process by allowing priority review. – Els Beirnaert, Aelin Therapeutics

The underlying technology was developed at the Switch laboratory of VIB by structural biologists Joost Schymkowitz and Frederic Rousseau. In their efforts to understand the misfolding of proteins, they discovered that the process is driven by the presence of short stretches of amino acids, called aggregation prone regions (APRs). Misfolded proteins “clump” and lose their function. Typically, protein folding research is focused on the prevention of this misfolding, which is implicated in neurodegenerative diseases. However, Schymkowitz and Rousseau realized that an opposite approach was also useful: by inducing the aggregation process with peptides matching APR sequences, disease associated proteins could be selectively knocked out.

Instead of focusing on a single problem, this fundamental research approach has resulted in a broad platform technology. “Being embedded in VIB made it possible to quickly assess the applicability of this new technology,” Beirnaert recalls. “The Switch team was matched with researchers with expertise in the target biology of different disease areas such as oncology, or infections with viruses, fungi and bacteria. This allowed us to gauge the value in different areas quickly.” In the context of these collaborations, the potential of Pept-ins™ as new antimicrobial agents was confirmed. The initial results have been very encouraging, both for Gram-positive and Gram-negative bacteria.

Harnessing the power of proteins

Initially, research was needed to ensure that the peptides, which are typically hydrophobic, were soluble and readily taken up by the cell. This led to the creation of Pept-ins™, based on a specific design around the APRs.

In the current market, the pharmaceutical industry is under pressure to sell as many doses as possible, to increase their revenue. This conflicts with our need to use last resort antibiotics sparsely, to prevent the spread of resistance. – Els Beirnaert, Aelin Therapeutics

By picking the right APRs, the selectivity of the Pept-ins™ can be engineered. This means that, when targeting a single disease-associated protein, an APR can be chosen that is unique to that protein, which prevents an interaction with other proteins and unwanted side-effects.

While most APRs are unique, a small minority occur in multiple proteins. For antimicrobial purposes, these kinds of cross-reactive APRs are selected. Targeting multiple proteins at the same time leads to a proteostatic collapse, killing the bacteria quickly and efficiently. This also means that resistance develops very slowly, if at all.

In addition to the fast kinetics of killing, bacteria would need to evolve multiple corrective mutations simultaneously to bypass the mechanism of action. As the selected APRs are specific to bacterial proteins, no side effects are expected. This is confirmed by initial results on in vivo infection models.

Supporting new solutions

Private investors strongly believe in the potential of new antimicrobials. – Els Beirnaert, Aelin Therapeutics

As the medical need for new antimicrobial strategies becomes increasingly clear, initiatives are being taken on different levels to accelerate their development. “Regulatory authorities like EMEA and FDA are streamlining the approval process by allowing priority review,” Beirnaert explains. “It is similar to the measures that have been taken to stimulate research on orphan diseases.”

On a political level, creative solutions are also being developed. “A few months ago, a bill was submitted to the US Congress that aims to revisit the business model,” Beirnaert continues. “In the current market, the pharmaceutical industry is under pressure to sell as many doses as possible, to increase their revenue. This conflicts with our need to use last resort antibiotics sparsely, to prevent the spread of resistance. In this new business model, companies could get a fixed fee in exchange for a set number of doses, giving them commercial security.”

Finally, the clinical development of new therapies is stimulated by increased funding. “Private investors also strongly believe in the potential of new antimicrobials,” Beirnaert states. “Our company is backed by a very reputable syndicate of investors. In addition, new specific initiatives arise; Novo Holdings has set up the REPAIR fund, dedicated to companies that offer ways of combatting Gram-negative bacteria. With a total budget of €145 million, they are acknowledging the severity of the issue, as well as the commercial potential. Finally, companies like Polyphor and Entasis have become listed on the stock market, attracting public funding.”

Aelin Therapeutics has attracted the interest of reputable investors, securing €27 million in a Series A financing round. The proceeds will be used to bring the Pept-in™ technology into the clinic. “The goal is to set up a Phase I study within 5 years,” Beirnaert says. “Naturally, we want to get this potential life-saving therapy to the patient as fast as possible, but there is still work to be done.”