University of Kansas investigators have played a key role in deciphering a previously unknown gene cluster chargeable for producing sartorial pyrones, chemicals made by a fungal pathogen, the family of which causes aspergillosis in humans. Is.
Their findings were recently published as a canopy story within the flagship journal of the Royal Society of Chemistry, a peer-reviewed journal.
Aspergillosis threatens the lives of greater than 300,000 people every year. A greater understanding of the genes chargeable for the chemicals — or “secondary metabolites” — produced by A. fumigatus and its fungal cousins ​​could help researchers develop more practical antifungal drugs.
“Fungal infections pose a significant challenge and have received much attention in the media, including in scientific reports,” said co-author Burl Oakley, the Irving S. Johnson Distinguished Professor of Molecular Biology at KU. “Among the problem organisms is a fungus known as “Where there may be a major number of individuals infected with AIDS, they are usually not getting treatment.”
Oakley and his co-authors were focused on how secondary metabolites are produced, which are sometimes considered for his or her medicinal potential – although they could be difficult to review within the laboratory – because they're so biologically lively. are
“Studies have identified several gene clusters in fungi that are responsible for producing these metabolites,” he said. “But these compounds are not usually produced under standard laboratory conditions, leaving many of their properties undetected. These metabolites, although not essential for an organism's growth, offer selective advantages. Secondary metabolites of these exhibit beneficial bioactivities for a variety of purposes, including immune suppression.”
To isolate and analyze the genes that express secondary metabolites, the team transferred a gaggle of those genes – called a biosynthetic gene cluster (BGC) – into the corresponding strain, then Enabled. Researchers have adapted a model fungal species for this system, referred to as “heterogeneous expression.”
“We can then observe the compounds they produce in the lab,” Oakley said. “In one example, a gene cluster revealed the synthesis of sartorial pyrones, a group of compounds for which there is previously limited information on their production.”
The research team named the gene cluster chargeable for these compounds “detective BGC” (standing for secretory pyrones). They analyzed compounds produced by spy BGC using high-resolution electrospray ionization mass spectrometry, nuclear magnetic resonance and microcrystal electron diffraction (microED) to discover 12 chemical products from spy BGC.
Oakley led the work with longtime colleague and corresponding writer Clay C. C. Wang of the University of Southern California. At KU, Oakley conducted research with C. Elizabeth Oakley and doctoral student Cory Jenkinson. Other co-authors were Shu-Yi Lin and Paul Seidler from USC. Yi Ming-Chiang from Taipei Medical University; Chung Kuo Lee, Christopher Jones and Hosea Nelson from the California Institute of Technology; and Richard Todd from Kansas State University
They report seven compounds not previously isolated.
“The spy BGC contains six adjacent genes involved in the biosynthesis of sartorypyrones,” they report. “We were able to propose a biosynthetic pathway for this family of compounds. Our method of refactoring the entire gene cluster in a dereplicated host system gives us a straightforward way to isolate the biosynthetic pathway. “
The same technique may lead to further advances in understanding and other fungal pathogens, Oakley said. The findings may lead to latest treatments for fungal infections in addition to environmentally friendly industrial applications. For example, one in every of Oakley's other lines of research used genetic modification to show ocean plastics into raw materials for the pharmaceutical industry.
“The current paper represents a proof of principle,” he said.
“We would like to express the rest of the secondary metabolite gene clusters so we can learn what each makes,” he said. “We know what makes 15 or more of them already. We know it's a serious pathogen, and we know some of the secondary metabolites that contribute to pathogenesis. But we know all the secondary metabolite genes. “Don't know the clusters. Get them out, then researchers can use that information to know the mechanism of infection therapeutically and find ways to limit infection.”
However, Oakley cautioned that the economic realities of developing antifungal drugs could prevent rapid development of latest drugs.
“We need more antibiotics and more antifungals,” he said. “But they're not profitable. A profitable compound is something they can give people for 30 years, not something you give for a week that solves the problem. So more financial. The incentive is not. You can come up with the best antibiotic in the world, they're going to put it on the shelf because it's going to be a last resort, and they're only going to use it when the others don't work. “