Researchers have hypothesized that the amount of time required to develop a novel antifungal therapeutic can be cut by repurposing drugs that are already FDA approved.
Treating invasive fungal infections can be a daunting and challenging task for clinicians. This task is complicated by the fact that there are only 3 classes of antifungal drugs and many human fungal pathogens have inherent or acquired resistance to these available options.
Investigators have hypothesized that the amount of time required to develop a novel antifungal therapeutic can be significantly reduced by repurposing drugs that are already US Food and Drug Administration approved.
In fact, mefloquine (MEF), which is an antimalarial, has previously been found to have modest antifungal activity. In a presentation at the ASM/ESCMID Conference on Drug Development to Meet the Challenge of Antimicrobial Resistance, a team of investigators presented their research exploring the antifungal activity of the antimalarial.
The study was conducted by investigators from the University of Rochester School of Medicine and Dentistry and the University of Iowa Carver College of Medicine. Their research explored the antifungal activity of both MEF and MEF analog molecules 2450, 4377, 13480, and 305758 to determine their potential as therapeutics for invasive fungal infections caused by Candida and Cryptococcus species.
The study team obtained the MEF analogs from the National Cancer Institute Development Therapeutics Program. Minimum inhibitory concentration (MIC) against susceptible reference strains and antifungal-resistant clinical isolates of Cryptococcus neoformas, Candida albicans, Candida glabrata, and Candida auris were determined using Clinical & Laboratory Standards Institute methods.
Methods also included characterizing interactions between clinical antifungals and analogs using the fractional inhibitory concentration index, assessing mitochondrial membrane potential via assay with MitoTracker Red CMXRos. Additionally, vacuoles were strained with FM4-64, capsule was induced with DMEM and stained with India ink, filamentation was induced with 1% FBS and human toxicity was determined by LDH release and XTT metabolism assays.
The team found that MICs for MEF ranged from 32-128 µg/ml and MEF analog MICs ranged from 1‐ 8 µg/ml in susceptible strains and 2-16 µg/ml in multidrug-resistant strains.
Fractional Inhibitory Concentration Index identified additive relationships with clinical antifungals.
“Though alone they are fungistatic, the combination of MEF or MEF analogs with fluconazole is fungicidal,” the authors write. “Mechanistic studies indicate analogs disrupt of capsule formation, filamentation, mitochondrial membrane potential, and cause of vacuolar defects.”
Overall, the toxicity to human cells was minimal and the initial structure-activity of MEF in this study identified potential candidate molecules that have in vitro activity against susceptible and resistant strains of Candida and Cryptococcus.
“The antifungal activity and drug-like properties of the MEF scaffold make it an attractive candidate for further investigation,” the authors conclude.
The poster, “Repurposing Mefloquine and Mefloquine Analogs to Treat Human Fungal Infections,” was presented in a poster session on Thursday, September 5, 2019, at ASM/ESCMID 2019 in Boston, Massachusetts.