Fungal killer: NMR reveals wall architecture

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  • Published: Aug 1, 2018
  • Author: David Bradley
  • Channels: NMR Knowledge Base
thumbnail image: Fungal killer: NMR reveals wall architecture

Antifungal

There are very few effective antifungal agents in the pharmaceutical arsenal and unfortunately, many types of fungal infection can kill. New research based on solid-state nuclear magnetic resonance (NMR) spectroscopy has looked at fungal cell wall and revealed details of its architecture that might be a new target for drugs to combat such infections.

There are very few effective antifungal agents in the pharmaceutical arsenal and unfortunately, many types of fungal infection can kill. New research based on solid-state nuclear magnetic resonance (NMR) spectroscopy has looked at fungal cell wall and revealed details of its architecture that might be a new target for drugs to combat such infections.

According to a team writing in the journal Nature Communications, "the fungal cell wall is a promising target as it contains polysaccharides absent in humans, however, its molecular structure remains elusive," they hope to remedy that situation with their NMR work. The research focused on the pathogenic fungus Aspergillus fumigatus and used glycosyl linkage analysis together with the NMR spectra assisted by dynamic nuclear polarization to reveal details about how chitin and α-1,3-glucan form a water-repellent, hydrophobic, scaffold surrounded by a hydrated matrix of diversely linked β-glucans and capped by a dynamic layer of glycoproteins and α-1,3-glucan in the fungal cell wall.

Leukaemia benefits

More than two million people are affected by potentially life-threatening fungal infections every year worldwide. One of the major challenges facing medicinal chemists and pharmaceutical science, however, is that the fungal cell wall, which could be a major target for novel drugs against such infections, remains something of a mystery. This has significantly impeded the development of effective antifungal medications. Now, chemist Tuo Wang of Louisiana State University in Baton Rouge, USA, and colleagues have identified for the first time the cell wall structure of one of the most prevalent and deadly fungi. Their work could lead to new pharmaceuticals that could save millions of lives.

A. fumigatus is an almost ubiquitous airborne fungus. Most people can cope with exposure to the pathogen, but for those with a compromised immune system, such as HIV/AIDS patients, those with leukaemia and other conditions, it can be lethal. The fungus multiplies at an extraordinary rate and affects more than 200,000 people each year, including one in four of all leukaemia patients. It kills more than half of them.

High-resolution fungal wall

"This is the first time anyone has looked at the whole cell of this fungus in its native state at such high resolution. Our work provides the molecular basis to engineer more effective antifungal drugs," Wang explains. Wang's team on this research included postdoctoral fellow Xue Kang, graduate students Alex Kirui and Malitha Dickwella Widanage, and undergraduate researcher Adrian Chen.

The researchers discovered that the hydrophobic and semi-waterproof core of Aspergillus fumigatus comprises two types of stiff sugar molecules that are bridged by other highly branched sugars and coated with a layer of a constantly changing sugar-protein mixture. The team's NMR work was carried out at the National High Magnetic Field Laboratory in Tallahassee, Florida. The unprecedented sensitivity and resolution allowed them to see the packing of molecules in their native state without perturbing them in the way that crystallisation for X-ray studies might.

The next stage will be to test the efficacy of various antifungal drugs against Aspergillus fumigatus developed on the basis of this discovery. The team is also characterizing other fungi in collaboration with Professor of Pediatrics and Microbiology Ping Wang in the Department of Microbiology, Immunology and Parasitology at the LSU Health Sciences Center in New Orleans.

"I want to share the structure and characterization of under-investigated complex carbohydrates because they are large, complex and difficult to understand. We are also establishing a method for rapidly screening the drug effects of various fatal fungi and guiding the development of better medicines," Wang adds.

Related Links

Nature Commun 2018, 9, 2747: "Molecular architecture of fungal cell walls revealed by solid-state NMR"

Article by David Bradley

The views represented in this article are solely those of the author and do not necessarily represent those of John Wiley and Sons, Ltd.

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