Starving drug-resistant fungal infections to death

Mira Edgerton, DDS, PhD, co-lead investigator of the study and research professor in the Department of Oral Biology at the UB School of Dental Medicine. Photo: Douglas Levere

Researchers repurpose drug to deny drug-resistant fungus of iron, an element crucial to its survival

How do you fight a fungal infection that is becoming increasingly resistant to medicine? By starving it, found a team of University at Buffalo and Temple University researchers.

To treat Candida albicans, a common yeast that can cause illness in those with weakened immune systems, researchers limited the fungus’ access to iron, an element crucial to the organism’s survival.

“In the absence of novel drug candidates, drug repurposing aimed at using existing drugs to treat diseases is a promising strategy.”
Mira Edgerton, research professor in the Department of Oral Biology at the UB School of Dental Medicine

They did so by using deferasirox, a medication used to treat blood disorders. Tested in mice, the results were promising: investigators decreased iron levels in saliva by four times, which altered the expression of more than 100 genes by the fungus, diminished its ability to infect oral mucosal tissue and caused a two-fold reduction in the organism’s survival rate.

“In the absence of novel drug candidates, drug repurposing aimed at using existing drugs to treat diseases is a promising strategy,” says Mira Edgerton, DDS, PhD, co-lead investigator of the study and research professor in the Department of Oral Biology at the UB School of Dental Medicine.

Edgerton, along with Sumant Puri, PhD, co-lead investigator and assistant professor in the Kornberg School of Dentistry at Temple University, published the study in March in Antimicrobial Agents and Chemotherapy.

Currently, only three major classes of clinical antifungal drugs exist. However, fungal drug resistance has steadily increased and no new classes of antifungals have emerged in decades, says Edgerton.

Candida albicans, a fungus among the group building resistance, is the agent behind a number of infections. They include oral thrush, a yeast infection in the mouth identified by a white film that coats the tongue and throat, causing painful swallowing; and denture-related stomatitis, a fungal infection that affects nearly two-thirds of U.S. denture wearers that causes inflammation, redness and swelling in the mouth.

The yeast is also the fourth leading cause of hospital-acquired bloodstream infections, which often have high mortality rates, says Edgerton.

Candida albicans is the most abundant fungus in the oral microbiome and relies heavily on saliva as a source for essential elements. Iron, the second most abundant metal in saliva, is a critical nutrient used by the fungus in several cellular processes, including energy production and DNA repair.

In mice, the group added deferasirox to drinking water to lower iron levels in saliva and reduce the availability of iron needed to sustain an infection.

The investigators found that Candida albicans in the mice who received the treatment were less likely to survive attacks by the immune system, subsisting at a 12 percent survival rate compared to a 25 percent survival rate in mice who did not receive the treatment.

The therapy also altered the expression of 106 genes by the fungus, a quarter of which were involved in the regulation of iron metabolism, directly regulated by iron or had iron-related functions. The study is the first report of iron starvation affecting gene expression of Candida albicans in real time during live infection, says Puri.

Other research has shown that treatment with deferasirox does not result in iron deficiency in adults with normal iron levels, forming the potential for preventative treatment for those who are also vulnerable to mucosal infections, says Puri.

Learn more: Drug-resistant infections: If you can’t beat ‘em, starve ‘em, scientists find

 

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A new approach to help the growing problem of antifungal drug resistance

Patrick Van Dijck and Adam Feyaerts

A research team at the VIB-KU Leuven Center for Microbiology has developed a novel screening method to identify antimicrobial properties of volatile substances. With this assay, they tested the vapour-phase-mediated activity of 175 essential oils (EOs) and 37 EO components. Approximately half of them proved active against the most drug-resistant type of Candida. In a context of fungi showing increasing drug resistance, these findings may be useful in both medical and agricultural applications.

The research project, led by prof. Patrick Van Dijck, is rooted in the growing problem of antifungal drug resistance. Candida cells, for example, are quickly becoming tolerant to fluconazole, the most-used antifungal drug. Next to exploring experimental new techniques, scientists also seek to repurpose existing substances. Plant essential oils (EOs), metabolites obtained by steam distillation or cold citrus peel pressing, may offer interesting opportunities: they are made up of compounds that help protect the plant against microbial or herbivore attacks.

Identifying EOs and their compounds

In the VIB-KU Leuven Center for Microbiology, Adam Feyaerts gathered a collection of 175 different EOs, constituting a collection of over one thousand different small molecules. The aim was to identify biologically active compounds present in these complex mixtures. They therefore developed a new class of assay that allowed to identify new volatile substances with antifungal activities over a distance.

Prof. Patrick Van Dijck (VIB-KU Leuven): “We screened our whole collection of EOs for vapor-phase mediated antifungal activity against two human fungal pathogens, Candida albicans and Candida glabrata. Interestingly, we found that approximately half of the EOs and their compounds had vapour-phase-mediated activity against bothCandida species. Surprisingly, C. glabrata, the most drug-resistant species of the two was on average even more susceptible. In contrast, none of the currently used antifungals showed any vapour-phase-mediated activity.”

Numerous potential applications

This is now the first simple test to look for the vapor-phase-mediated antimicrobial activity of molecules. The same assay could also be used to test other biological activity. And although these findings still have to be confirmed in clinical trials, potential applications are numerous.

Co-author Adam Feyaerts (VIB-KU Leuven): “Our findings are for instance a starting point for the development of molecules that could also be used in vaporizers. After all, volatiles can access otherwise hard to reach areas. Think of possibilities such as maintaining hygiene in hospitals or treat patients with lung infections. There are agricultural options too, such as preventing post-harvest contamination or protecting crops against pests.”

Learn more: Plant-derived volatiles may serve as future antifungals

 

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A new drug compound kills drug-resistant superbug C. auris

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Microscopic yeast have been wreaking havoc in hospitals around the world—creeping into catheters, ventilator tubes, and IV lines—and causing deadly invasive infection. One culprit species, Candida auris, is resistant to many antifungals, meaning once a person is infected, there are limited treatment options. But in a recent Antimicrobial Agents and Chemotherapy study, researchers confirmed a new drug compound kills drug-resistant C. auris, both in the laboratory and in a mouse model that mimics human infection.

APX001, the prodrug of the active moiety APX001A, is currently in clinical development by Amplyx Pharmaceuticals. It works through a novel mechanism of action. Unlike other antifungal agents that poke holes in yeast cell membranes or inhibit sterol synthesis, the new drug targets an enzyme called Gwt1, which is required for anchoring critical proteins to the fungal cell wall. This means C. auris can’t grow properly and has a harder time forming drug-resistant fungal biofilms that are a stubborn source of hospital outbreaks. Gwt1 is highly conserved across fungal species, suggesting the new drug could treat a broad range of fungal infections.

“The drug is first in a new class of antifungals, which could help stave off drug resistance. Even the most troublesome strains are unlikely to have developed workarounds for its mechanism of action,” said study lead Mahmoud A. Ghannoum, PhD, professor of dermatology at Case Western Reserve University School of Medicine and director of the Center for Medical Mycology at Case Western Reserve University and University Hospitals Cleveland Medical Center.

In the new study, Ghannoum’s team tested the drug against 16 different C. auris strains, collected from infected patients in Germany, Japan, South Korea, and India. When they exposed the isolates to the new drug, they found it more potent than nine other currently available antifungals. According to the authors, the concentration of study drug needed to kill C. auris growing in laboratory dishes was “eight-fold lower than the next most active drug, anidulafungin, and more than 30-fold lower than all other compounds tested.”

The researchers also developed a new mouse model of invasive C. auris infection for the study. Said Ghannoum, “To help the discovery of effective drugs it will be necessary to have an animal model that mimics this infection. Our work helps this process in two ways: first we developed the needed animal model that mimics the infection caused by this devastating yeast, and second, we used the developed model to show the drug is effective in treating this infection.”

Ghannoum studied immunocompromised mice infected with C. auris via their tail vein—similar to very sick humans in hospitals who experience bloodstream infections. Infected mice treated with APX001 and anidulafungin had significant reductions in kidney and lung fungal burden two days post-treatment, compared to control animals. APX001 also significantly decreased fungal burden in the brain, consistent with brain penetration, whereas reduction with anidulafungin did not reach significance. The results suggest the new drug could help treat even the most invasive infections.

According to Ghannoum, the most exciting element of the study is that it brings a promising antifungal one step closer to patients. It helps lay the foundation for phase 2 clinical trials that study that study the safety and efficacy of new drugs in patients with fungal infections. There is an urgent need for such studies, as C. auris infection has become a serious threat to healthcare facilities worldwide—and resistance to commercially available antifungal drugs is rising.

“Limited treatment options calls for the development of new drugs that are effective against this devastating infection,” Ghannoum said. “We hope that we contributed in some way towards the development of new drugs.”

Learn more: New Antifungal Provides Hope in Fight Against Superbugs

 

 

 

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Researchers Identify New Class of Antifungal Agents

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Serious fungal infections cause 1.3 million deaths annually worldwide.

Researchers have identified a new class of antifungals to treat the more than 300 million people worldwide who develop serious fungal infections

The research is described in the current issue of mBio, the online open-access journal of the American Society for Microbiology.

“Fungal infections are a significant cause of morbidity and mortality worldwide and current antifungal drugs have drawbacks. These new drugs may pave the way for the development of a new class of antifungals,” said principal investigator Maurizio Del Poeta, MD, a professor in the Department of Molecular Genetics and Microbiology at Stony Brook University, Stony Brook, New York.

Fungal infections are most commonly found in individuals with medical conditions that compromise the immune system, such as AIDS, or individuals who are being treated with immunosuppressives, such as those battling cancer. The three classes of antifungal drugs currently available—azoles, polyenes, and echinocandins—are far from optimal.

“Even with treatment, the mortality rate of invasive fungal infections is over 50%,” said Dr. Del Poeta. “The drugs don’t work that well. They are toxic, so they affect other organs, and they are static, meaning they may be able to stop a fungus from replicating but they are not able to kill the fungus.” Current antifungals also have a narrow spectrum of activity, and some interact with other drugs such as chemotherapy agents and immunosuppressants.”

Previous research has shown that when fungal cells lack a lipid called glucosylceramide (GlcCer), they are unable to replicate. Seeking to exploit this weakness and develop a new class of antifungals, an international group of researchers screened a synthetic drug library for compounds that target the synthesis of fungal but not mammalian GlcCer. “The enzymes that are important for the synthesis of fungal glucosylceramide are different than the ones important for the synthesis of mammalian glucosylceramide,” said Dr. Del Poeta. “We thought that because the pathway is totally different, we could specifically target the fungal  glucosylceramide without affecting mammalian glucosylceramide, and that is exactly what we did.”

They identified two compounds, BHBM and its derivative DO, that decreased levels of fungal but not mammalian glucosylceramide. In test tube and animal studies, these compounds were highly effective against several pathogenic fungi and were well tolerated in animals. The drugs were effective when used alone or in combination with other classes of antifungals. The researchers plan to spend the next five years fine-tuning their research and identifying even more effective compounds that inhibit fungal glucosylceramide.

Serious fungal infections cause 1.3 million deaths annually worldwide. The most common and life-threatening fungal infections are cryptococcosis, candidiasis, aspergillosis, and pneumocystosis.

Read more: Researchers Identify New Class of Antifungal Agents

 

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