Light-activated molecular machines have been developed by chemists and shown to drill holes through the membranes of gram-negative and gram-positive bacteria, killing them in as little as two minutes. Their research suggests a possible new strategy for combating antibiotic-resistant bacteria, which lack natural defenses against mechanical invaders.
|To treat infections, visible light activates molecular machines.
Molecular machines that kill infectious bacteria have been taught to reconsider their mission.
The most recent iteration of Rice University's nanoscale drills is activated by visible light rather than ultraviolet (UV), as in previous versions. These have also been shown to be effective at killing bacteria in tests on real infections.
Rice chemist James Tour and his team successfully tested six molecular machine variants. In as little as two minutes, they all punched holes in the membranes of gram-negative and gram-positive bacteria. Bacteria have no natural defenses against mechanical invaders, so resistance was futile. As a result, they are unlikely to develop resistance, potentially providing a strategy for defeating bacteria that have become resistant to standard antibacterial treatments over time.
"I tell my students that by the time they're my age, antibiotic-resistant bacteria will make COVID look like a walk in the park," Tour said. "Antibiotics will not be able to save the lives of 10 million people who die each year from bacterial infections. But this completely deters them."
The groundbreaking study, led by Tour and Rice alumni Ana Santos and Dongdong Liu, has been published in Science Advances.
Because prolonged UV exposure can be harmful to humans, the Rice lab has spent years refining its molecules. The new version is powered by still-blueish light at 405 nanometers, which spins the molecules' rotors at a rate of 2 to 3 million times per second.
Other researchers have suggested that light at that wavelength has mild antibacterial properties on its own, but the addition of molecular machines amplifies it, according to Tour, who believes that bacterial infections like those suffered by burn victims and people with gangrene will be early targets.
The machines are based on the work of Nobel Laureate Bernard Feringa, who created the first molecule with a rotor in 1999 and got the rotor to spin reliably in one direction. Tour and his colleagues published their advanced drills in Nature in 2017.
The Rice lab's initial tests on burn wound infection models confirmed the new molecules' ability to quickly kill bacteria, including methicillin-resistant Staphylococcus aureus, a common cause of skin and soft tissue infections that killed over 100,000 people in 2019.
By adding a nitrogen group, the team was able to activate visible light. "The molecules were further modified with different amines in either the stator (stationary) or rotor portion of the molecule to promote the association between the machines' protonated amines and the negatively charged bacterial membrane," said Liu, who is now a scientist at Arcus Biosciences in California.
The machines also effectively break up biofilms and persister cells, which go dormant to avoid antibacterial drugs, according to the researchers.
"Even if an antibiotic kills the majority of a colony, there are often a few persister cells that do not die," Tour explained. "But it makes no difference to the drills."
The new machines, like previous versions, promise to resurrect antibacterial drugs that were thought to be ineffective. "Drilling through the membranes of microorganisms allows otherwise ineffective drugs to enter cells and overcome the bug's intrinsic or acquired resistance to antibiotics," said Santos, who is in the third year of a postdoctoral global fellowship that began at Rice and is now continuing at the Health Research Institute of the Balearic Islands in Palma, Spain.
The lab is working to improve bacterial targeting to reduce damage to mammalian cells by attaching bacteria-specific peptide tags to drills to direct them toward pathogens of interest. "However, even without that, the peptide can be applied to a bacterial concentration site, such as a burn wound area," Santos explained.
Rice alumni Anna Reed and John Li, senior Aaron Wyderka, graduate students Alexis van Venrooy and Jacob Beckham, researcher Victor Li, postdoctoral alumni Mikita Misiura and Olga Samoylova, research scientist Ciceron Ayala-Orozco, lecturer Lawrence Alemany, and Anatoly Kolomeisky, a professor of chemistry, are co-authors, as is Antonio Oliver of the Health Research Institute of the Balearic Islands
Tour is the T.T. and W.F. Chao Professor of Chemistry as well as a materials science and nanoengineering professor.
The research was funded by the European Union's Horizon 2020 research and innovation program (843116), the Discovery Institute, and the Robert A. Welch Foundation (C-2017-20190330).
Materials provided by Rice University. Originally written by Mike Williams. Note: Content may be edited for style and length.
Ana L. Santos, Dongdong Liu, Anna K. Reed, Aaron M. Wyderka, Alexis van Venrooy, John T. Li, Victor D. Li, Mikita Misiura, Olga Samoylova, Jacob L. Beckham, Ciceron Ayala-Orozco, Anatoly B. Kolomeisky, Lawrence B. Alemany, Antonio Oliver, George P. Tegos, James M. Tour. Light-activated molecular machines are fast-acting broad-spectrum antibacterials that target the membrane. Science Advances, 2022; 8 (22) DOI: 10.1126/sciadv.abm2055