Nanobots against antibiotic-resistant bacteria?

Doctor Ana Santos looks back with emotion at a significant period in her life: her grandfather and uncle died several years ago of a urinary infection, and the death of a close friend from an ‘infected cut’.

These deaths shocked her deeply. In the days of antibiotics such misfortunes were not to happen.

The rise and fall of antibiotics

“Members of my family were dying of infections,” said Ms. Santos, a microbiologist at the Balearic Islands Health Research Institute, or IdISBA, in Spain. “I began to realize that we were going backwards: our antibiotics were no longer effective.”

It is a global problem. According to the Medical Journal, in 2019, nearly 5 million deaths worldwide were linked to antibiotic-resistant microbes. The Lancet.

Six types of resistant bacteria do the most damage. According to the World Health Organization, Drug resistant diseases May be the direct cause of 10 million deaths by 2050.

Ms Santos has set out to tackle these alarming figures by leading an EU-funded research project which aims to develop microscopic machines capable of killing resistant bacteria. title RebellionThe project lasted for 39 months and was completed in April 2023.

“I got this concept of molecular machines that make holes in cells,” Ms. Santos said. “We need to start getting creative.”

In 1928, Scottish doctor Alexander Fleming discovered the first true antibiotic, penicillin, made by a specific type of mold. Other antibiotics, often made by soil microbes, were later discovered, saving millions of lives.

But in what was effectively an arms race, microbes managed to develop defenses to avoid antibiotics.

Machines that make holes in bacteria

At the time two of his relatives and a friend had lost their lives to infection, Santos was studying how bacteria lived and died under conditions of starvation. Then she decided to redirect her research.

“I was very frustrated because I was faced with an immediate problem and I couldn’t do anything about it,” she explained. “More and more people are dying from antibiotic-resistant infections.”

She asked researchers specializing in the field to lend a hand and teamed up with a Spanish group to trial how small molecular machines pierce bacteria. Machines are made of two parts of chemically joined atoms. Under the influence of light, the upper part begins to rotate rapidly like a drill bit.

Antibiotics often wrap around specific bacterial proteins, like a key fits a lock. Problem: The bacteria can undergo a physical change so that the key no longer fits the lock. Antibiotics stay out.

The advantage of nanomachines is that bacteria are more difficult to survive.

Ms. Santos advanced these bacteria-killing machines through Project Rebellion.

Machines that kill superbugs

Both parts of these machines measure less than 100 nanometers, or one-thousandth the width of a human hair. Their size is insignificant compared to bacteria.

In her laboratory, Ms. Santos released millions of her nanomachines into a cluster of bacteria. The machines bound to the bacteria and, once exposed to light, began to spin and pierce them.

In front of her microscope, Ms. Santos was delighted: Bacterial cells were bursting with tiny pores.

Further experiments revealed that this tiny drill can kill a range of strains that commonly infect humans.

She then tried something else: a small number of machines against methicillin-resistant Staphylococcus aureus, or MRSA, a notorious and particularly deadly superbug. A lower concentration of machines will reduce the risk of damage to human cells.

The tools made enough holes in the MRSA that it was again susceptible to antibiotics.

“It is very difficult for bacteria to develop resistance to this action,” Ms Santos said. “It’s like we’re bombarding them.”

Machines that heal wounds

To deploy this new weapon against resistant bacteria, researchers must ensure that the nanomachines are safe for patients. This involves selectively targeting bacteria but not human cells.

One of the first reasons to be optimistic is that nanomachines are positively charged. Therefore, they prefer to bind to negatively charged bacteria rather than more neutral human cells.

In Ms. Santos’ experiments on worms, the nanomachines did not harm human cells after being injected. Eager to bring this strategy closer to patients, she is preparing the next step: conducting safety tests on mice.

If successful, the first patients treated may be those with infected wounds, particularly burn victims, who are prone to infection.

The nanomachines can be placed on their skin and, activated by light, pierce the bacteria infecting the wound.

The best European team

Nanomachines are regularly in the news.

Professor Ben Feringa of the University of Groningen, Netherlands, won the Nobel Prize in Chemistry in 2016 for his nanomachines with molecular motors that can be activated by ultraviolet radiation.

Molecules change shape when struck by light. So they can serve as switches or triggers. Mr. Feringa even built one Nanocar Contains a molecule capable of moving along the copper surface.

He helps oversee an EU-funded research project that trains young scientists in molecular machines. title BiomolmaxThe project spans four and a half years and will end in June 2024.

Although not yet available in hospitals, nanomachines have the potential to treat cancer patients in ways that have scientists and doctors excited. Current anti-cancer drugs often cause side effects such as hair loss, nausea, fatigue or immune weakness. This is because drugs can damage healthy cells.

We can imagine that one day nanomachines will deliver cell-killing drugs precisely targeting patients’ cancers, perhaps finding their way into any tumor.

Maria Vicente, a professor at the Biomedical Research Foundation in Valencia, Spain, oversees the BIOMOLMACS project, which designs small carriers to deliver drugs to breast cancer cells.

Jan van Haste of Eindhoven University of Technology in the Netherlands is also overseeing the project. He is developing materials that can be used to transport vaccines or nanomedicines inside cells, especially those that are cancerous.

Mr Van Hest, Ms Vicente and Mr Feringa can count on the help of other leading researchers from other European countries who bring their own expertise.

Professor Ramsey Besser of the University of Warwick in the UK is creating polymer nanoparticles to deliver future gene therapies to specific locations in patients’ bodies. The particles are often coated sugars because they have the ability to act as keys to open cells in the body.

“These synthetic sugars can interact with the cell membrane and provide the key for the particle to open the door and insert the gene into the cell,” explained Baker, who mentors two junior scientists and coordinates the entire project with 15 doctoral students.

Also in the UK, Professor Robin Shattock of Imperial College London is working on lipid nanoparticles, tiny spheres made of fat that can safely enter cells. Lipid nanoparticles are the breakthrough that has made it possible to develop a vaccine against Covid-19.

New talents

Students of these leading European researchers may be the next wave of medical researchers.

“The next big change for the pharmaceutical industry will be training our genes to prevent or fight cancer,” Baker said.

According to him, the BIOMOLMACS project can prepare scientists for careers in specific companies that develop nanomachines that will be used for such biological treatments in specific organs.

Meanwhile, Ms Santos, through the REBELLION project, hopes her work can also make a difference to cancer patients who are more susceptible to bacterial infections due to their treatment.

“My friend beat cancer but then died of an infection,” she said. “I still remember when the doctor said that bacteria is resistant to everything and there is nothing that can be done.”

Their goal is that doctors never have to say those words again.

The research presented in this article was funded by the EU through the Marie Skodowska-Curie Actions (MSCA). The views of the interviewees do not necessarily reflect those of the European Commission.

More information

This article was originally publishedthe horizonEU magazine dedicated to research and innovation.