From the mold on a shower curtain to the floor of the gym locker room to the dirt in the backyard, people are exposed to many types of fungi every day. Most of the time, the fungi are harmless, but lung infections caused by breathing in the spores of the fungus Histoplasma capsulatum are on the rise.
Humans and fungi share similar proteins, a biological bond that makes curing fungal infections difficult — and expensive. Current costs to treat these stubborn infections can top $10,000 per patient, and yet for more than 20 years, no one has developed new classes of antifungal drugs.
My colleagues and I at The Ohio State University Wexner Medical Center have discovered a new compound that could be developed as an antifungal drug to treat histoplasmosis and cryptococcosis, two types of fungal infections that are naturally resistant to some existing antifungal drugs.
Generally, people with weakened immune systems are more likely to develop life-threatening fungal infections, however healthy people are affected as well. Like tuberculosis, Histoplasma infects healthy hosts, attacks their lungs, and can lie dormant in immune cells for years, later causing reactivation disease. It commonly causes respiratory infections, and in rare cases, histoplasmosis can cause blindness, joint pain, or life-threatening complications including heart problems.
Unlike most fungi, Histoplasma is particularly good at avoiding detection by the body's immune system and surviving the body's immune response. Respiratory histoplasmosis causes flu-like symptoms, often making diagnosis difficult. People with histoplasmosis have been mistakenly diagnosed with colds, the flu and even lung cancer — it depends on how familiar a physician is with histoplasmosis.
There are an estimated 100,000 Histoplasma infections each year in the United States. Histoplasma capsulatum spores are found across a broad stretch of the Midwest and southern United States. The CDC estimates that 80 percent of people who live in the region have been exposed, and that nearly 10 to 25 percent of all AIDS patients living in these areas will develop a histoplasmosis.
The antifungals physicians currently use to treat the infection may require patients take the medications for months — and the regimens have undesirable toxic side effects that require monitoring by a doctor.
Our team set out to find a new drug that would target the fungus without harming the human host. We received pilot funding from Ohio State's Center for Clinical and Translational Science (CCTS) and the Public Health Preparedness for Infectious Diseases Program (PHPID) in 2012 to do this.
My colleagues and I searched a library of commercially-available, small molecules looking for agents that inhibited the growth of fungal, but not human, cells.
To speed the selection process, we engineered Histoplasma cells with a fluorescent protein that made the cells glow red while inside of a living macrophage — the type of mammalian immune cell that Histoplasma attacks, and in which it reproduces. As the number of fungal cells increased inside the macrophage, so did the fluorescence, and consequently, the cells would glow brighter. However, when a cell was exposed to an active compound that prevents Histoplasma reproduction, the brightness did not increase. This allowed us to quickly determine — in Histoplasma's natural host cell environment — efficacy and toxicity of each drug candidate we tested.
Not only were we able to visually screen thousands of compounds in just a few weeks, but we were also able to measure each compound's impact in a real (not simulated), live, host cell. We narrowed drug candidates down to a primary candidate called 41F5, which is 60 times more toxic to fungal cells than human cells.
Our work was recently published in September's Antimicrobial Agents and Chemotherapy.
Now, I am working with a medicinal chemist at Ohio State to see if we can enhance the selectivity and toxicity profile of the drug further for additional testing. There are people here in the United States and around the world suffering from varying degrees of histoplasmosis that need a safer, and better, treatment option. Our pilot study outcomes and methods are very encouraging, and I'm hopeful that with additional funding from the National Institutes of Health, we'll be able to keep moving at this accelerated pace.
The views expressed are those of the author and do not necessarily reflect the views of the publisher. This article was originally published on LiveScience.