Scientists are still diligently looking for ways to tackle the threat of antibiotic resistance. And there may be a task for… gold.

At first glance, gold, “the king of metals,” may not seem like an obvious treatment for a bacterial infection. Still, scientists have been recognizing the antimicrobial properties of specially modified gold nanoparticles for several years now. To date, however, they have failed to resolve some of the key issues associated with this. At least, until now.

To damage

In a report from the World Health Organization last year, scientists stated that “antibiotic resistance has risen dangerously in all parts of the world.” Not only did they sound the alarm at the time, they also called for more investment in ways to deal with this problem. One such way is through gold nanoclusters – each made up of about 25 gold atoms – that punch holes in the cell walls of bacteria, weakening their resistance to antibiotics.

While that sounds promising, there are still some challenges to overcome. Because how do you get these active gold nanoparticles to the site of a bacterial infection, without damaging the healthy cells of the host (such as a human being)?

Wrapped up

In a new study researchers tackled the problem. How? By using the electrostatic forces of nature. Bacterial cell walls are in fact more negatively charged than mammalian cells. Believing that opposite charges attract, the researchers packed the gold nanoclusters into a molecule called a “ligand,” which is positively charged. Similar to a carrier pigeon, this ligand delivers the nanoclusters to the bacterial cell wall, where it disrupts the cell membrane.

Toxic

But then there is another problem. “Highly positively charged nanoparticles are known antibacterial materials, but they are too toxic to host cells,” explains Dejian Zhou in an interview with Scientias.nl from. To protect the host cells, the scientists added a second ligand to the ‘wrapper’ that wraps around each nanocluster. These molecules have both positive and negative charges – known as zwitterions – and are also found in the lipids of mammalian cell membranes. “So these zwitterionic ligands reduce toxicity,” Zhou said. It means that these ligands make the gold nanoclusters more compatible with the host mammalian cells. “We were able to find the most optimal ligand ratio, with low toxicity to healthy tissues while still having excellent antibacterial activity,” concluded Zhou.

The gold nanocluster in the molecular wrapper. The ligands in blue are the zwitterionic ones, while those in red are positively charged. Image: University of Leeds

The new ‘jacket’ of the gold nanoclusters means that they still make short work of bacteria, while they are less harmful to our own bodies. The gold penetrates into the bacterium, while the researchers use their method to prevent the gold particles from also penetrating our own cells.

Resistant bacteria

The team then decided to test their newly fabricated nanoclusters for bacterial strain Staphylococcus aureus (MSRA). The MRSA bacterium is insensitive (resistant) to treatment with the antibiotic meticillin; a commonly used drug. The researchers tested three antibiotics against MRSA with and without the gold nanoclusters. In the cases where the antibiotic was used in combination with the gold nanoclusters, the researchers discovered an enhanced antimicrobial effect. In fact, with one class of antibiotics, there was a 128-fold decrease in the amount of antibiotic needed to inhibit the growth of MRSA. And that means the newly designed jacket works. “By systematically tuning the ratio of the two ligands, we found a way to use gold nanoclusters,” Zhou says. “In addition, it not only acts as an effective antimicrobial agent, it also enhances the action of antibiotics on resistant bacteria.”

Gold nanoclusters

It means that the tiny gold nanoclusters the researchers fabricated in their study make bacteria visibly more sensitive to antibiotics. “Resistant bacterial membranes often show reduced antibiotic permeability,” Zhou explains. “But our gold nanoclusters can effectively disrupt the bacterial cell membrane and kill the bacterium. In addition, this process also makes the bacterial membrane more permeable to antibiotics, making it easier for these drugs to penetrate into the bacterial cells. This makes the bactericidal effect even stronger.”

Antibiotic resistance

They are promising results. Because it means that the researchers here may have discovered a surprising new weapon in the fight against antibiotic resistance. And that is desperately needed. For example, about 700,000 people still die each year from infections that could still be treated with antibiotics in the 1960s and 1970s. And by 2050, the number of annual deaths could even reach ten million. However, the search for new antibiotics is difficult. But as this study shows, there are other ways to deal with the problem. “Concentrating solely on designing new antibiotics will not solve the problem,” Zhou said. “Bacterial resistance to such new variants will be inevitable. We need to pay more attention to developing new approaches to revitalize our current antibiotic arsenals. This can be a cheaper, faster and possibly more sustainable solution.”

And that’s exactly what the researchers tried to do with their study. “Our findings provide a highly effective, cheaper, and faster alternative to address the challenge of antibiotic resistance,” said Zhou. “Our gold nanoclusters even work against resistant bacteria. And that means that they can not only play an important role in the treatment of resistant bacterial infections, but also contribute to solving the looming antibiotic resistance.”