Drill-down of treatment-resistant bacteria using molecular machines

Fungi are present on the skin of about 70% of the population, but cause no harm or benefit. Some fungal infections, such as athlete’s foot, are mild.Others, such as Candida albicanscan be fatal, especially for people with weakened immune systems.

Fungal infections are on the rise due to an aging population and increasing prevalence of chronic diseases. At the same time, fungi are becoming more resistant to treatment. As a result, fungal infections can quickly become a serious public health threat.

In 2022, the World Health Organization released its first-ever “Priority Fungal Pathogen List,” calling for increased surveillance, public health interventions, and the development of new antifungal agents.

We are a multidisciplinary team of chemists and biologists charting new avenues to tackle drug-resistant infections. We use tiny nanoscale drills that fight harmful pathogens at the molecular level. As the traditional antimicrobial research pipeline struggles, our approach has the potential to revitalize the fight against these stubborn infections.

Molecular machines as alternative antifungal agents

Physicians urgently need new antifungal drugs, but finding them is challenging. First, fungi share many similarities, making it difficult to develop drugs that selectively kill fungi without harming human cells.

Second, when drugs are misused or overused, fungi can rapidly develop resistance to multiple antifungal drugs at once. Therefore, developing antifungal drugs is far less profitable for pharmaceutical companies than developing drugs to treat chronic diseases such as diabetes and high blood pressure, which require long-term use.

One solution to this problem may lie in the Nobel Prize-winning technology of molecular machines.

Molecular machines are synthetic compounds that rotate their components at high speeds, about 3 million times per second, when illuminated by light. Doctors can use glow-tipped probes to activate these molecular machines to treat internal infections, or use lamps for skin infections. The light causes the machines to spin, and the spinning motion causes the machines to puncture and perforate cell membranes and organelles, resulting in cell death.

Our group used this technology for the first time to kill cancer cells in 2017. To target the appropriate cells, molecular machines can be linked to specific peptides that only bind to the cells of interest, making it possible, for example, to target specific cancer types. Since then, we have used these molecules to kill bacteria, destroy tissue, and stimulate muscle contraction. These properties make molecular machines attractive candidate technologies to address the growing fungal threat.

Diagram showing the structure of a molecular machine as gray lines connected to several hexagonal shapes
3D structure of a molecular machine. A molecular machine consists of a rotor (upper) part and a stator (lower) part connected by a central axis. Following light activation, molecular machinery rapidly rotates and punctures the fungal cell.
Rice University Tour Lab

Testing antifungal molecular machines

Researchers first tested the ability of light-activated molecular machines to kill fungi. Candida albicans. This yeast-like fungus can cause life-threatening infections in immunocompromised people.Molecular machines die out compared to conventional drugs C. albicans much faster.

Subsequent research found that molecular machines could also kill other fungi. Aspergillus fumigatus Dermatophytes are a type of fungus that cause infections of the skin, scalp, and nails. Molecular machines have also removed fungal biofilms, communities of slimy, antimicrobial-resistant microorganisms that adhere to surfaces and commonly cause medical device-related infections.

Unlike conventional antifungal drugs, which target fungal cell membranes and cell walls, the molecular machinery is localized to fungal mitochondria. Mitochondria, often referred to as the “cell’s powerhouses,” generate the energy that drives other cellular activities. Molecular machines destroy fungal mitochondria when activated by visible light. When a fungal cell’s mitochondria stop functioning, the cell loses its energy supply and dies.

Two black-and-white electron microscope images of fungal cells. The image on the left shows a large, round, healthy cell, while the cell on the right is shrinking after treatment with a light-activated molecular machine.
Candida albicans Before and after exposure to photoactivated molecular machines.Puncture by molecular machine C. albicansIt destroys cell walls and intracellular organelles, ultimately killing fungal cells.
Matthew Meyer/Rice University.

At the same time, molecular machines also interfere with the tiny pumps that remove antifungal drugs from cells, preventing them from fighting back. Fungi are unlikely to develop defenses against this process, as these molecular machines act by mechanical rather than chemical mechanisms.

In laboratory experiments, combining light-activated molecular machines with conventional antifungal drugs also reduced the amount of fungus in the body. C. albicans– Infected worms and pig claws rubrum ringworm fungusis the most common cause of athlete’s foot.

A New Frontier for Fighting Fungal Infections

These results suggest that combining molecular machines with conventional antifungal drugs can improve existing therapies and provide new options for treating resistant strains. This strategy may also help reduce the side effects of conventional antifungal agents, such as gastrointestinal disturbances and skin reactions.

Fungal infection rates may continue to rise. Therefore, the need for new treatments will continue to grow. Climate change is already causing the emergence and spread of new human pathogenic fungi, including: Candida auris. C. Auris It is often resistant to treatment and spreads rapidly in healthcare facilities during the COVID-19 pandemic. An overstretched healthcare system, overuse of immunosuppressants, and misuse of antibiotics have all been linked to epidemics of infectious diseases, according to the Centers for Disease Control and Prevention. C. Auris.

In the future, researchers may be able to use artificial intelligence to create better antifungal molecular machines. Using AI to predict how different molecular machines will interact with fungal and human cells will lead to a safer and more effective way to specifically kill fungi without harming healthy cells. can develop effective antifungal molecules.

Antifungal molecular machines are still in the early stages of development and not yet available for routine clinical use. But continued research raises hopes that these machines could one day offer better treatments for fungal and other infections.

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