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Combing the ocean for antimicrobials, scientists at the University of Wisconsin-Madison have discovered a new antifungal compound that effectively targets multi-drug-resistant strains of deadly fungi without toxic side effects in mice.
The new molecule was discovered in the microbiome of a sea sketch from the Florida Keys as part of an effort to identify new antimicrobials from poorly studied ecosystems. Scientists named the antifungal turbinmicin, after the sea sketch from which it was isolated, Ecteinascidia turbinate.
Pathogenic fungi continue to develop resistance to the small number of drugs available to combat them. As a result, more people die from previously treatable diseases, such as candidiasis or aspergillosis, which are caused by common fungi that sometimes become virulent. The identification of compounds such as turbinmicin is the key to the development of new and effective drugs. However, although turbinmicin is a promising drug candidate, further studies of the molecule and extensive preclinical research need to be performed before a new drug can become available.
A collaboration of UW-Madison chemists, biologists, and doctors published their findings Nov. 19 in the journal Science. The discovery of turbinmicin is the most tangible result of the group’s $ 30 million five-year grant from the National Institutes of Health to harvest new useful antimicrobial drugs from bacteria living in neglected environments.
Most of the existing antimicrobials have been isolated from soil bacteria. As scientists continued to probe these bacteria for new drugs, they often discovered the same molecules over and over again.
“Bacteria in particular are rich sources of molecules. But many of Earth’s ecosystems have been heavily undermined for drug discovery,” says Tim Bugni, a professor at the UW-Madison School of Pharmacy who led the turbinmicin project. “There is immense bacterial diversity in the marine environment and it has barely been studied.”
To correct that oversight, Bugni teamed up with UW School of Medicine infectious disease and public health professor David Andes, UW-Madison bacteriology professor Cameron Currie, and their colleagues to search for neglected ecosystems. Specifically, they sought to discover new bacteria from marine animals and then test them for new types of antimicrobial compounds.
To identify turbinmicin, the research team began by harvesting ocean invertebrates from the Florida Keys between 2012 and 2016. From these animals, they identified and cultured nearly 1,500 strains of actinobacteria, the same group of bacteria that produced many clinical antibiotics. Using a screening method, they prioritized 174 strains to be tested against drug-resistant Candida, an increasingly prominent and dangerous disease-causing fungus. Turbinmicin stood out for its effectiveness.
“Candida auris in particular is quite unpleasant,” says Bugni. Almost half of patients with systemic Candida infection die. “The Candida auris strain we targeted in this article is resistant to all three classes” of existing antifungals.
The researchers tested the purified turbinmicin against a list of 39 fungi isolated from patients. These strains represented different species and encompassed all known ways in which fungi developed resistance to existing drugs. In laboratory experiments, turbinmicin stopped or killed nearly all fungal strains at low concentrations, indicating a powerful effect.
Similar experiments on mice infected with drug-resistant strains of Candida auris and Aspergillus fumigatus also demonstrated the ability of turbinmicin to attack resistant fungi. Since fungi and animals are closely related, and therefore share a similar cellular mechanism, antifungals can prove toxic to animals as well. However, turbinmicin showed no toxic side effects in mice, even at concentrations 1000 times higher than the minimum dose. The effective dose would be tens of milligrams for an average weight adult, lower than that of many other antibiotics.
Based on yeast experiments conducted by UW-Madison genetics professor Anjon Audhya, turbinmicin appears to affect the cell packaging and organizational system of fungi. Turbinmicin blocks the action of the Sec14p protein, with the end result that yeast like Candida cannot sprout to reproduce. Other types of fungi, when exposed to turbinmicin, may have difficulty moving cell content to grow.
Researchers have filed a patent for turbinmicin and have now turned their attention to improving the molecule by making small changes to its structure that could increase its effectiveness as a drug. The turbinmicin discovery also serves as proof of concept for collaborative efforts to explore new ecosystems and select thousands of candidates to identify new and effective antimicrobial candidates.
“We now have the tools to select candidates, find promising strains and produce molecules for doing animal studies,” Bugni says. “This is the key to targeting multi-drug resistance: unique molecules are needed.”
This work was supported in part by the National Institutes of Health (grants U19 AI109673, U19 AI142720, R35 GM134865 and R01 AI073289).
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