Finding new drugs with fungi

NIH grant will help researchers learn ways to counter drug resistance via gene editing

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HOUSTON—Rice University scientists recently won federal support for their pursuit of novel drugs to treat disease in the form of a five-year National Institutes of Health grant. The $1.9-million grant will fund the lab of biomolecular engineer Xue Sherry Gao of Rice’s George R. Brown School of Engineering as they use CRISPR-Cas genome editing to facilitate drug discovery based on natural fungus.

”We will take advantage of the recent emerging CRISPR genomic manipulation tool kits to study natural product biosynthesis in fungi, and increase the repertoire of novel fungal natural products,” Gao, who is the Ted N. Law Assistant Professor of Chemical and Biomolecular Engineering at Rice, tells DDN.

The team plans to deepen their understanding of how enzymes in fungi synthesize useful compounds and use the knowledge to create CRISPR-based toolkits to characterize the genes responsible and adapt them for novel drug development.

”More than 60 percent of the small-molecule drugs approved by the FDA are derived from natural sources,” said Gao. “We want to explore how nature builds these complex small-molecule scaffolds, the most famous example of which is the antibiotic penicillin, which saves millions of lives. A lot of organisms are hard to culture in laboratory conditions, but filamentous fungus is a rich resource for drugs, and relatively easy to grow in the lab. If you leave food on your kitchen counter during the summer in Houston, you know what I mean.”

“We will firstly focus on filamentous fungus, but [will] potentially apply these CRISPR tools to other types of fungi in the near future,” she adds.

The grant came through after the lab published a paper in Angewandte Chemie that outlines how the team plans to attack the problem. The study, which was led by Gao and Rice postdoctoral research associate Fanglong Zhao, employed genetic manipulations to modify the fungus strain and discover the mechanism that produces quinolone-gamma-lactam, a small molecule found in filamentous fungi.

“Quinolone and g-lactam are both important pharmacophores in many clinical drugs and have been extensively studied. The scaffold of quinolone-g-lactam hybrid represents a new pharmacophore structure and has the potential to combat the increasing crisis of multidrug resistance,” explains Gao. “We want to know how nature synthesizes this quinolone-gamma-lactam hybrid ring.”

Gao believes that using the hybrid as a scaffold for novel drugs could greatly speed their development.

“Quinolactacins are a class of tricyclic quinolone (quinolin-4-one) alkaloids which are commonly produced by filamentous fungi,” she notes. “To date, several quinolactacins, including quinolactacin A1, A2, B1, B2, C1, C2, D1 and D2 have been isolated from Penicillium genus (J. Antibiot., 2000, 53, 1247-1251.; Org. Biomol. Chem., 2006, 4, 1512-1519.). Among them, quinolactacin A2 exhibits inhibitory activity against acetylcholinesterase (AChE) and tumor necrosis factor (TNF) production (J. Antibiot. 2001, 54, 831-835.; J. Antibiot. 2000, 53, 1247-1251).

“AChE plays a pro-aggregating (non-catalytic) role to accelerating β-amyloid peptide aggregation and deposition into the fibrils (Neuron, 1996, 16, 881–891), thus inhibition of AChE is one of the most successful therapeutic strategy for the symptomatic treatment of Alzheimer’s disease and its progression. Several AChE inhibitors such as donepezil, rivastigmine, galantamine, and tacrine have been developed for symptomatic treatment of Alzheimer’s disease (Prog. Neuro-Psychopharmacol. Biol. Psychiatry., 2001, 25, 27-57.; Drug Develop. Res., 2002, 56, 347-353.); therefore, quinolactacins A2 might potentially be developed as anti-Alzheimer’s drug candidate.”

And that’s not the only area in which there’s some potential, according to Gao: “Quinolactacin A2 also exhibits TNF inhibitory activity (J. Antibiot. 2000, 53, 1247-1251.). TNFα is a vital cytokine involved in inflammation, immunity, and cellular organization. In addition, some pre-clinical findings suggest that TNFα may promote cancer development and progression, which has led to propose anti-TNF therapy as a novel approach to anti-tumor treatment (Lancet, Oncol 2003, 4: 565–73). Several trials have been set up to investigate the role of TNFα antagonists in cancer, providing a rationale for their clinical use (Expert. Rev. Anticancer Ther., 2002; 2: 277–86; Clin. Cancer Res., 2004, 10, 6528-6534). The TNF inhibitory activity of quinolactacin A2 makes it a viable therapeutic the target for cancer treatment.”

Editing the genomic DNA of the host fungus has helped the researchers pinpoint genes responsible for programming the hybrid molecules. The researchers expect the grant to help them expand on that success.

“Only when we deleted the essential gene responsible for the synthesis of this molecule did we see it disappear,” explained Gao. “Once we understand how enzymes synthesize this small molecule, we’re able to do enzyme engineering to produce different products that could be even better than the natural ones.”

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