Multi-drug resistant Candida auris no match for novel compound
January 11, 2018
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.”
For more information about Case Western Reserve University School of Medicine, please visit: case.edu/medicine.
Hager, et al. “In vitro and in vivo Evaluation of the Antifungal Activity of APX001A/APX001 Against Candida auris.” Antimicrobial Agents and Chemotherapy.
The novel drug compound was originally synthesized at Eisai Co. Ltd., in Tokyo, Japan, and is now owned by Amplyx Pharmaceuticals, who helped fund the study. Development of the new mouse model was supported in part by Scynexis Incorporated, Cidara Therapeutics, and Amplyx Pharmaceuticals.
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