Molecular machines combat infections
Antibiotics have marked a significant landmark in the battle against infectious diseases. However, the widespread and indiscriminate use of these drugs in clinical practice has led to the emergence of antibiotic resistance, one of the most significant health challenges of the 21st century. Currently, antibiotic resistance is responsible for more than 1.5 million deaths globally each year, incurring great healthcare costs.
Light-activated nanomaterials target bacteria
There are very few new antibiotics with a novel mode of action under clinical development by the pharmaceutical industry. This makes most antibiotics in the pipeline susceptible to the same resistance mechanisms observed in previously developed molecules. In light of this, the REBELLION project developed nanoscale synthetic molecules known as molecular machines as an alternative to antibiotics. The work was undertaken with the support of the Marie Skłodowska-Curie Actions (MSCA) programme and focused on light-activated molecular machines that can be controlled with spatial and temporal precision by modulating the intensity and wavelength of the light stimulus. “These minuscule powerhouses could provide the much-needed edge in our battle against superbugs, redefining how we combat infections in our rapidly changing landscape,” highlights the MSCA Research Fellow Ana L. Santos. When activated by specific wavelengths of light, these molecular machines undergo rapid conformational changes that result in a unidirectional, spin-like rotation, like that of a drill. This drilling motion can propel molecules through lipid bilayers, causing cell death. Molecular machines have previously been shown to target and kill cancer cells. However, a major limitation was the need for UV light for activation, which is toxic to human cells. Santos and colleagues overcame this obstacle by changing the chemical structure of the molecular machines so that they responded to safe, visible blue light while retaining their mode of action.
Eradicating microorganisms in minutes
In the laboratory, molecular machines were able to kill a wide range of bacterial and fungal pathogens, including antibiotic-resistant strains such as methicillin-resistant Staphylococcus aureus. This occurred within minutes of light activation, outperforming conventional antimicrobials. To eliminate bacteria, the molecular machines bind to their membranes and mechanically perforate them upon light activation, causing fatal rupture of cells. In fungi, molecular machines accumulate in mitochondria and pierce through their membranes, sabotaging energy production and causing cell death. “Remarkably, the pathogens do not appear to develop resistance, indicating that the physical antimicrobial effect of molecular machines is fundamentally different from conventional drugs that bind to specific molecular targets and against which resistance can readily evolve with only a few mutations,” explains Santos. Molecular machines also proved remarkably effective against resistant phenotypes, such as biofilms and persister cells – dormant cells that can tolerate conventional antimicrobials, which typically target metabolic processes related to active growth. Since molecular machines mechanically destroy microbial membranes through a process that is not dependent on the cell's metabolic activity, they can effectively eradicate these difficult-to-treat phenotypes.
Combining molecular machines with other agents
Molecular machines can also be used to improve the efficacy of conventional antimicrobial agents. As they permeabilise and weaken the membranes of microbes, they facilitate the uptake of antimicrobial drugs into cells. Additionally, they inhibit efflux pumps that expel drugs out of the cell, and therefore increase intracellular drug concentration. “While further research is necessary to optimise the therapeutic application and ensure safety, molecular machines represent a paradigm shift in our approach to infectious diseases,” concludes Santos.
Keywords
REBELLION, antibiotics, infectious disease, antibiotic resistance, light activation, molecular machines, bacterial membrane, mitochondria