Light-activated molecular machines fight antimicrobial resistance

A selective weapon that can be remotely controlled to kill bacteria independently or in concert with current antibiotic approaches.

Antimicrobial resistance is a challenge on the smallest scale, but with the highest stakes. As our use of antibiotics has grown, in life-saving hospital procedures, in practical treatments suppressing all manner of infections, and on livestock around the world, bacteria have risen to the challenge, adapting to escape our attacks.

Losing our ability to fight bacterial infections would mean millions of deaths and a big step backwards for humanity. New antibiotics and better management of those currently used to limit resistance are essential, but progress on both fronts has been slow compared to the urgency of the threat.

To fight superbugs and keep everyday infections from becoming deadly, we may need new weapons.

Light-activated molecular machines

Molecular machines could be a powerful addition to our arsenal. Researchers at Rice University have developed tiny synthetic engines that can launch attacks on bacteria in ways they may never encounter in nature and are therefore ill-equipped to repel them.

The small devices are built around a switch that reacts to light, causing rapid movement when activated. This movement can be either a continuous jerk between two different poses, or a circular rotation that turns molecules into drills that pierce bacteria’s protective membranes. Previous research has found success with the drilling approach, but these bacterial rams can be a bit indiscriminate in their action.

Now the team has developed a new iteration of the molecular machines that weaken bacteria in a different way. In an article published in Advanced sciences, the researchers describe experiments revealing that this version – built around a light-sensitive switch made of hemithioindigo – was more devastating to bacteria when performing the flip motion than the drill. This suggests that the mode of action this time around was not based on pure physical strength, but something else.

More than just rams

Early tests revealed they selectively killed Gram-positive bacteria, a type of bacteria that includes the persistent superbug MRSA, which plagues hospitals, but not Gram-negative bacteria. When molecules switch between the two positions, they disrupt the matter around them and generate highly reactive chemicals called reactive oxygen species. These weaken the bacteria, causing their walls to thin and their internal contents to leak out.

“These do not kill cells by mechanically tearing membranes like the previous ones [molecular machines] do,” said one of the Rice University study authors, James Tour. “They induce enough disruption that reactive oxygen species and free radicals are generated and eventually kill the cells. It’s not the rapid necrotic death that we’ve seen before. It’s a bit slower , but it is extremely effective.

This can lead directly to colony collapse of bacteria, including lingering cells and biofilms, which can outlast conventional therapies, causing resurgence and gradually developing dangerous resistance each time they encounter and survive. a wave of antibiotics. The new machines also help prime the bacterial population for easy attack with existing antibiotics.

A selective weapon against antimicrobial resistance

The approach appears to work on Gram-positive bacteria only due to major differences in the membrane structure of Gram-positive and negative bacteria. Mammalian cells have equally robust defenses against bacteria-damaging oxidative stress due to differences in the electrical charge of their membranes and the stiffening presence of cholesterol, which means the risk of collateral damage to the patient is reduced. .

“An important advantage of these molecules is that they have a narrow spectrum of activity and selectively kill a specific group of bacteria: Gram-positive bacteria,” said the paper’s co-senior author Ana Santos. “Therefore, they are less likely to cause the side effects seen with broad-spectrum antibiotics that indiscriminately kill ‘bad’ and ‘good’ bacteria, and they are also less likely to lead to resistance because only one group of bacteria is affected. ”

A selective weapon that can be remotely controlled using visible light and capable of killing bacteria independently or in concert with current approaches without harming human cells is an enticing prospect. Beyond laboratory experiments, a potential use would be for burns. These exposed wounds are often infected with stubborn Gram-positive bacteria and prone to reinfection and the development of resistance. And a light-activated solution is especially handy on the surface of the skin.

Early tests in a model species were promising: MRSA-infected moth larvae could only survive seven days with treatment with both antibiotics and hemithionidigo machines; conventional treatments alone were not enough.

There’s a lot of work to be done to move from treating moth burns in the lab to tackling the global crisis of antimicrobial resistance, which was the third leading cause of death worldwide in 2019 and could claim ten million lives. each year by 2050 if nothing is done. But perhaps the light that activates these molecular machines is a beacon of hope for the future.

Reference: Ana Santos, James Tour, et al., Hemithioindigo-Based Visible Light-Enabled Molecular Machinery Kills Bacteria Through Oxidative Damage, Advanced Sciences (2022). DOI: 10.1002/advs.202203242

Image credit: Michael Schiffer on Unsplash

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