Deepening in fungi resistant to treatment with molecular machines

The 3D structure of a molecular machine. The molecular machine consists of rotor (top) and stator (bottom) portions connected by a central shaft. Upon activation of the light, the molecular machines spin rapidly, piercing the fungal cells. Credit: Tour Lab, Rice University

Fungi are present on the skin of about 70% of the population, without causing harm or benefit. Some fungal infections, like athlete’s foot, are minor. Others, like Candida albicans, can be deadly – ​​especially for individuals with weakened immune systems.

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

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

We are an interdisciplinary team of chemists and biologists charting a new path to fight drug-resistant infections. We’re using tiny nanoscale drills that fight harmful pathogens at the molecular level. As the traditional antimicrobial research pipeline struggles, our approach has the potential to rejuvenate the fight against these persistent infections.

Molecular machines as alternative antifungals

While doctors urgently need new antifungal drugs, developing them is challenging. First, it is difficult to develop drugs that selectively kill fungi without harming human cells because of their many similarities.

Second, fungi can quickly develop resistance to multiple antifungal drugs at once when drugs are used inappropriately or excessively. As such, antifungal drug development is far less rewarding for pharmaceutical companies than drug development for chronic diseases such as diabetes and hypertension that require long-term use.

A solution to this problem could lie in a Nobel Prize-winning technology: molecular machines.

Molecular machines are synthetic compounds that rapidly spin their components at about 3 million times per second when exposed to light. Doctors can use a light-tipped probe to activate these molecular machines to treat internal infections or a light bulb for skin infections. The light makes the machines spin, and this rotational motion pushes them to pierce and perforate the cell membranes and organelles, which results in cell death.

Our group used this technology for the first time to kill cancer cells in 2017. To target the right cells, the molecular machines can be linked to specific peptides that bind only to the desired cells, allowing, for example, the targeting of specific types of cancer . Since then, we’ve used these molecules to kill bacteria, destroy tissue, and stimulate muscle contraction. These properties make molecular machines an attractive candidate technology for dealing with the growing threat of fungi.

Deepening in fungi resistant to treatment with molecular machines

Candida albicans before and after being exposed to light-activated molecular machines. Molecular machines perforate the cell wall and intracellular organelles of C. albicans, eventually killing the fungal cell. Credit: Matthew Meyer/Rice University

Testing antifungal molecular machines

The researchers first tested the ability of light-activated molecular machines to kill fungus in Candida albicans. This yeast-like fungus can cause life-threatening infections in immunocompromised people. Compared to conventional drugs, the molecular machines killed C. albicans much faster.

Subsequent studies have found that the molecular machines can also kill other fungi, including fungi such as Aspergillus fumigatus and dermatophyte species, the types of fungi that cause infections of the skin, scalp and nails. Molecular machines have even eliminated fungal biofilms, which are slimy, antimicrobial-resistant communities of microorganisms that attach to surfaces and often cause infections associated with medical devices.

Unlike conventional antifungals, which target the fungal membrane or cell wall, the molecular machines are located in the fungal mitochondria. Often called the “powerhouses of the cell,” mitochondria produce energy to fuel other cellular activities. When activated with visible light, the molecular machines destroy fungal mitochondria. Once the fungal cell’s mitochondria stop functioning, the cell loses its energy supply and dies.

At the same time, the molecular machines also stop the tiny pumps that remove antifungal agents from the cell, thus preventing the cell from fighting back. Because these molecular machines act mechanically rather than chemically, it is unlikely that fungi will develop defenses against this treatment.

In laboratory experiments, combining light-activated molecular machines with conventional antifungal drugs also reduced the amount of fungus in worms infected with C. albicans and in pig nails infected with Trichophyton rubrum, the most common cause of athlete’s foot.

New frontiers to fight yeast infections

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

Yeast infection rates will likely continue to rise. As such, the need for new treatments will only become more urgent. Climate change is already causing the emergence and spread of new human pathogenic fungi, including Candida auris. C. auris is often resistant to treatment and spreads rapidly in healthcare facilities during the COVID-19 pandemic. According to the Centers for Disease Control and Prevention, overwhelmed healthcare systems, overuse of immunosuppressants, and misuse of antibiotics have all been implicated in C. auris outbreaks.

In the future, researchers will be able to use artificial intelligence to create better antifungal molecular machines. By using AI to predict how different molecular machines will interact with fungi and human cells, we can develop safer and more effective antifungal molecules that specifically kill fungi without harming healthy cells.

Antifungal molecular machines are still in the early stages of development and are not yet available for routine clinical use. However, ongoing research gives hope that these machines may one day provide better treatments for yeast infections and other infectious diseases.

Provided by The Conversation

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Deepening in fungi resistant to treatment with molecular machines

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