Fungal infections, a growing threat to global health, have long been difficult to treat, especially as many fungi develop resistance to existing medications. However, recent research from Duke University School of Medicine offers promising new strategies in the fight against these resilient pathogens. By identifying a key enzyme involved in fungal survival, Duke scientists have opened the door to potential new treatments that could save millions of lives.
The enzyme’s role in fungal biology and survival
The research at Duke centers on the trehalose biosynthesis pathway, a process critical for fungal survival, especially at high temperatures like those found in the human body. The enzyme trehalose-6-phosphate synthase (Tps1) plays a crucial role in this pathway, enabling fungi to produce trehalose—a disaccharide composed of two linked glucose molecules. Trehalose acts as a protective shield, allowing fungi to withstand harsh conditions and thrive in environments like the human body, where they can cause serious infections.
Cryptococcus neoformans, a particularly dangerous fungus, relies heavily on this pathway. This pathogen can cause fatal brain infections, especially in immunocompromised individuals, such as those with HIV or those who have undergone organ transplants. Disrupting the trehalose biosynthesis pathway presents a novel approach to weakening these deadly fungi and preventing infections.
How the researchers identified the enzyme
The Duke research team, led by Dr. Erica J. Washington and Dr. Richard G. Brennan, focused on uncovering the detailed structure of the Tps1 enzyme. They employed cryo-electron microscopy (cryo-EM), a powerful technique that allows scientists to visualize proteins at near-atomic resolution. Unlike traditional methods like X-ray crystallography, which require protein crystallization, cryo-EM can reveal the structure of complex proteins, even those with disordered regions.
Using cryo-EM, the team was able to visualize the Tps1 enzyme from Cryptococcus neoformans, discovering that it forms a homo-tetramer—a complex structure composed of four identical subunits. This detailed understanding of the enzyme’s structure is crucial, as it suggests that disrupting the formation of this complex could effectively inhibit the trehalose pathway, crippling the fungus’s ability to survive in the human body.
Potential impact on treating fungal infections
The implications of this research are far-reaching. While the primary focus has been on Cryptococcus neoformans, the insights gained from studying the trehalose pathway could be applied to other dangerous fungi, such as Candida albicans and Aspergillus. Both are known to cause severe infections, particularly in immunocompromised patients and are becoming increasingly resistant to current treatments. Candida auris, a multidrug-resistant fungus identified as a significant threat by the World Health Organization, could also be targeted by new treatments developed from this research. Given the high mortality rates associated with these infections, the discovery of a new drug target like Tps1 is a critical step forward.
Broader implications for public health
Fungal infections account for approximately 1.5 million deaths annually, with many more individuals hospitalized due to severe infections. As climate change continues to drive the evolution of fungi, making them more thermotolerant and, therefore, more capable of surviving in the human body, the need for new antifungal strategies becomes ever more urgent.
The Duke team’s research not only offers hope for developing new drugs that can specifically target fungal pathogens without harming human cells, but it also highlights the broader importance of understanding fungal biology in the context of a changing environment. As fungi continue to adapt, this kind of foundational research will be essential for staying ahead of potential new threats.
Next steps for the Duke research team
The Duke University research team is now focused on advancing their findings by developing compounds that can specifically disrupt the Tps1 enzyme’s activity. The ultimate goal is to create new antifungal drugs that can effectively target the trehalose biosynthesis pathway without causing side effects in humans. Given the critical need for new antifungal treatments, the next phase of this research will likely involve collaboration with pharmaceutical companies to bring these potential therapies to clinical trials. By targeting the trehalose biosynthesis pathway, scientists have identified a promising new avenue for treatment that could save countless lives, particularly as the threat of drug-resistant fungal infections continues to grow.
