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Mar 06, 2023

Can This Shape

Antibiotic resistance is one of the leading public health concerns and one that

Antibiotic resistance is one of the leading public health concerns and one that the U.S. Centers for Disease Control and Prevention calls a "global threat."

In the United States alone, antibiotic-resistant strains of bacteria cause more than 2.8 million infections that kill more than 35,000 people per year. The issue is even greater in developing countries, where rates of infectious disease are high and antiobiotic access is often limited.

Now a new study published this month from researchers in the United States, the United Kingdom, and Australia presents an innovative approach to addressing the issue of antibiotic resistance — through the development of shape-shifting antibiotics.

"What we’ve done is taken a last-line defense antibiotic, vancomycin, and attached it to a very unique shapeshifting molecule called bullvalene," Josh Homer, PhD, coauthor of the new study and a research investigator at Cold Spring Harbor Laboratory (CSHL) in Laurel Hollow, New York, told Healthline.

"I like to describe it as kind of like a Rubik's cube that can change its form. When we attach two vancomycin units to this Rubik's cube in the middle, those vancomycin units can kind of dance around in a way that allows them to occupy different spaces," he said.

The researchers tested multiple forms of their shape-shifting antibiotics against vancomycin-resistant bacteria in wax moth larvae. They found the shape-shifting compounds were significantly more effective than standard vancomycin at clearing the drug-resistant infections.

The bacteria also showed no signs of developing resistance to the shape-shifting antibiotics.

"The new molecules were able to evade the resistance mechanism, which is a very exciting finding," said Homer.

Antibiotic resistance happens when bacteria evolve to survive drugs designed to kill them.

This can lead to bacterial infections that are very difficult to treat.

"Drug-resistant infections are a serious threat to modern medicine," Mark Blaskovich, PhD, Director of Translation at the Institute for Molecular Bioscience and co-founder of the institute's Centre for Superbug Solutions at the University of Queensland in St Lucia, Australia, told Healthline.

"If antibiotics no longer work, medical treatments that we take for granted — such as hip replacements, C-sections, cancer treatments — will no longer be tenable," he said. Even routine medical procedures carry a risk of complications, which often include bacterial infections.

Blaskovich said developers aren't creating new antibiotics quickly enough to stay ahead of antibiotic resistance.

One of the primary challenges is the standard funding model for drug development, which heavily relies on investment from pharmaceutical companies. These companies are typically reluctant to invest in drugs such as antibiotics that are unlikely to generate a quick profit.

"The financial rewards for antibacterials are not large for pharma [companies]," Shahriar Mobashery, PhD, Navari Family Professor in Life Sciences in the Department of Chemistry and Biochemistry at the University of Notre Dame in Indiana, told Healthline.

"Furthermore, antibiotics cure infections in short [treatment courses] of typically 10-14 days. Pharma [companies] are in search of chronic ailments, for which drugs are taken for a lifetime — such as high blood pressure, high cholesterol, etcetera," he said.

Homer hopes that innovative approaches to repurposing existing antibiotics will help address this issue.

"I think one of the most exciting things about this [shapeshifting antibiotics] project is that we’re using drugs that are already out there and repurposing them," he said.

The development of shape-shifting antibiotics is being led by John E. Moses, PhD, a professor and researcher at the CSHL Cancer Center who has been working with his own lab and collaborators in the UK and Australia to synthesize and test the novel drugs.

To create each molecule of shape-shifting antibiotic, members of his team have used a type of chemical reaction known as click chemistry to combine two units of conventional vancomycin with a core of bullvalene.

Combining two molecules of vancomycin produces what's known as a vancomycin dimer.

"Many other studies have previous reported the development of vancomycin dimers, often with more potent activity [against antibiotic-resistant bacteria] than this study," Blaskovich, who was not involved in this study, said.

"But the unique component of this research is using a ‘shapeshifting’ linker, a chemical moiety that exists in multiple structural forms," he continued. "The new molecule has substantially less propensity than vancomycin to cause one type of bacteria to develop resistance and was able to treat an infection in an insect model."

The linker bullvalene is a fluxonial molecule, which means its atoms can swap positions. This allows it to change shape in over a million possible configurations.

This may provide an adaptive advantage against ever-evolving bacteria, resulting in a vancomycin dimer that's particularly resilient against antibiotic resistance.

However, more research is needed to fine-tune the shape-shifting compounds, evaluate their effectiveness over a longer period of time, and learn whether they’re safe in other animal models and in humans.

Moses’ team is currently working to optimize the new antiobiotics, with the hopes of making them more potent.

"I’m working in the lab to make small structural changes to see if we can improve upon the activity of the compounds," said Homer. "Then after that, we would have to go through the standard drug evaluation and approval process to look at toxicity and effectiveness."

Conventional vancomycin can damage liver and kidney cells in humans, which has become a growing issue as antibiotic-resistant bacteria require larger and larger doses of the drug to treat.

The new shape-shifting antibiotics were only effective at relatively large doses, which may pose a safety concern if they are found to be as toxic as conventional vancomycin.

Although more research is needed, Homer said the early findings are promising.

"We evaluated toxicity against kidney cells and liver cells and found that compared to vancomycin, our lead candidate molecules were less toxic," he said. "This is definitely a promising start."