Infections with multi-resistant fungi pose an increasing risk to human health. In their search for new active ingredients, researchers have struck gold in the microbiome of marine life: a bacterium that colonizes sea squirts produces a fungicide that effectively combats various types of fungi that are pathogenic to humans. The fungicide, which the researchers christened Turbinmicin, was even shown to be effective against infections with the multi-resistant fungus Candida auris. The new active ingredient also proved to be well tolerated in mice. Further studies should now clarify to what extent Turbinmicin can be used in humans.
Almost two million people die each year from fungal infections. The trend is increasing, because currently only three different classes of active ingredients are available for combating, and more and more fungal strains are developing resistance to these. The fungus Candida auris, which was discovered in 2009 and spreads as a hospital germ and can cause fatal infections, especially in immunocompromised patients, is in some cases even resistant to all currently known fungicides. The American health authority CDC therefore lists Candida auris as an acute threat.
Searching for active ingredients in little-explored environments
A team led by Fan Zhang from the University of Wisconsin-Madison has now identified a promising new active ingredient that has been shown to be effective against Candida auris and other fungal infections in laboratory and animal tests: the fungicide Turbinmicin. It is a natural molecule produced by a bacterium that lives on sea squirts. “Bacteria are rich sources of molecules. But many of the terrestrial ecosystems have already been used quite heavily for drug discovery, ”says Zhang’s colleague Tim Bugni. Those who search in these heavily researched areas often only find active ingredients that are already known.
In order to discover completely new active ingredients, Bugni’s team therefore looked in a previously neglected environment: “There is an immense bacterial diversity in the sea and this has hardly been investigated so far,” says Bugni. From 2012 to 2016, the researchers collected marine animals in the Florida Keys and examined their microbiome. In doing so, they identified almost 1,500 different actinobacteria – a widespread class of bacteria from which several antibiotics have been obtained in the past. The researchers selected 174 bacterial strains for further analysis based on their chemical diversity. Using a screening process, they tested the extent to which molecules produced by the bacteria help against fungi such as Candida auris.
Highly effective and well tolerated
A molecule that the researchers named Turbinmicin turned out to be particularly effective. In 39 samples from patients with various fungal infections, Turbinmicin fought the harmful fungi even at low concentrations and avoided all known resistance mechanisms. “This indicates that there is no cross-resistance and that Turbinmicin potentially has a different mechanism of action than the previously known fungicides,” the researchers write.
Zhang and colleagues also used mice to test the safety and effectiveness of the newly discovered agent in vivo. Since many cellular processes in fungi, animals and humans are similar, new fungicides often fail because they turn out to be toxic. Turbinmicin, however, did not cause any side effects in any of the treated mice – even at a dose 1000 times the concentration required for treatment. At the same time, it was very effective in fighting the fungal disease.
According to studies by the researchers, the mechanism of action is probably based on the fact that Turbinmicin blocks the protein Sec14p, which is vital for fungi. This is responsible for transport processes within the fungal cells. Without Sec14p the cells cannot multiply and eventually perish. Because this target is specific to fungi, side effects are less likely than with other fungicides. Before Turbinmicin can be further developed for use in humans, further safety studies are required, in which the agent is tested in other animal species and with extended periods of use.
Starting point for new therapies
If it does prove to be safe and effective, it could be a useful therapy option for patients with multi-drug resistant fungal infections. The discovery of the new drug candidate also shows that the researchers’ idea of looking for drugs in so far little-explored ecosystems works in principle. “Success in developing effective new therapies depends on creative approaches, including those that take advantage of the chemical diversity in nature that has evolved over millions of years of evolution,” said Leah Cowen of the University of Toronto in an in Perspective on the study published in the journal “Science”.
Bugni adds, “Now we have the tools to sort candidates, find promising strains, and produce molecules for animal studies. That is the key to fighting resistance: you need unique molecules. “
Source: Fan Zhang (University of Wisconsin-Madison) et al., Science, doi: 10.1126 / science.abd6919