A novel drug compound has demonstrated promising results in the fight against drug resistance, particularly in Candida auris infection, according to a study from Case Western Reserve University (OH, USA).
Pathogenic yeast species such as C. auris are responsible for millions of potentially fatal infections worldwide, with treatment options limited by multidrug resistance. The novel compound, termed APX001A, is the first in a new class of antifungals utilizing a novel method of action: rather than puncturing the cell membrane of yeast or inhibiting their ability to synthesize sterols, the new drug prevents the attachment of essential proteins to the yeast cell wall.
The drug targets a C. auris enzyme, Gwt1, by preventing the synthesis of glycosylphosphatidylinisotol (GPI)-anchored wall transfer proteins, thereby limiting growth and preventing the formation of drug-resistant communities. Interestingly, the enzyme is highly conserved across fungal species, suggesting it may be effective as a target in multiple infections.
In the study, the team tested the drug on 16 different strains of C. auris, obtained from infected individuals in Germany, South Korea, Japan and India. APX001A was observed to be more effective against the isolates than nine other currently available treatments. Furthermore, the concentration of the compound needed to kill the yeast was eight-fold lower than the next most powerful drug, anidulafungin, and more than 30-fold lower than all other compounds examined.
The drug was also tested in vitro using mouse models infected with C. auris. Survival rates for APX001A group ranged from 80% to 100%, whilst anidulafungin treatment led to 50% survival. Additionally, mice treated with APX001A exhibited significant reductions in levels of colony forming units in the brain, kidneys and lungs within 2 days of treatment, compared with mice treated with anidulafungin, indicating that the drug may be able to combat even the most advanced infections.
The results of the study hold promise for the development of medications capable of treating drug-resistant C. auris infections, as summarized by study author Mahmoud A. Ghannoum (Case Western University): “Limited treatment options call for the development of new drugs that are effective against this devastating infection. We hope that we contributed in some way towards the development of new drugs.”
Sources: Hager CL, Larkin EL, Long L, Abidi FZ, Shaw KJ, Ghannoum MA. In vitro and in vivo evaluation of the antifungal activity of APX001A/APX001 against Candida auris. Antimicrob. Agents Chemother.doi: 10.1128/AAC.02319-17 (2018); http://casemed.case.edu/cwrumed360/news-releases/release.cfm?news_id=906