Fungal infections are a growing public health concern because the fungi that cause them are becoming increasingly resistant to the drugs designed to eliminate them. This phenomenon, known as antifungal resistance, occurs when a fungus evolves the ability to withstand a medication that was previously effective. The rise in resistance is driven by several factors, including the overuse of antifungal medications in both humans and agriculture.
Target Site Alteration
Antifungal drugs function with high specificity, much like a key fits a particular lock. They work by binding to a specific molecule, or target site, within the fungal cell to disrupt a vital process. A primary resistance mechanism involves altering this target site through genetic mutation. This change modifies the shape of the target protein or enzyme—the “lock”—so the drug “key” no longer fits, rendering the medication useless.
For example, azole antifungals inhibit an enzyme needed to produce ergosterol, a component of fungal cell membranes. A single point mutation in the ERG11 gene, which codes for this enzyme, can alter its structure enough to prevent azole drugs from binding effectively.
These mutations can arise spontaneously in a fungal population. When exposed to an antifungal drug, cells with the mutation survive and multiply, leading to a resistant infection. This selection process allows a random genetic event to become a widespread clinical problem as the resistant strain proliferates under drug pressure.
Active Drug Efflux
Fungi can actively pump antifungal drugs out of their cells before they cause harm using specialized proteins in the cell membrane called efflux pumps. These pumps act like molecular bouncers, recognizing and expelling harmful substances from the cell’s interior. This process requires energy, which the fungus expends to protect itself.
Resistance occurs when a fungus enhances its pumping capacity through genetic changes. It can increase the number of efflux pumps or produce more efficient ones. This upregulation removes the drug faster than it can enter, preventing it from reaching an effective concentration inside the cell.
Two families of efflux pumps, the ATP-binding cassette (ABC) superfamily and the major facilitator superfamily (MFS), contribute to this resistance. In the pathogen Candida albicans, for example, the overexpression of genes for pumps like CDR1 and MDR1 is a documented cause of resistance to azole drugs. By producing more of these pumps, the fungus overpowers the medication.
Biofilm Formation
Many fungi form structured communities called biofilms, which provide a collective defense against antifungal treatments. A biofilm is a dense aggregation of fungal cells that adhere to a surface, like a medical implant or human tissue. These cells are encased within a protective, self-produced matrix of polysaccharides, proteins, and DNA.
This matrix acts as a physical barrier, preventing drugs from penetrating deep into the biofilm. The matrix can also bind to drug molecules, sequestering them in the outer layers. As a result, cells in the interior are exposed to lower, non-lethal drug concentrations, allowing them to survive.
Additionally, fungal cells within a biofilm exist in different metabolic states. Cells in the deeper layers may be slow-growing or dormant, making them less susceptible to drugs that target actively growing cells. This community-level defense makes biofilm-related infections difficult to eradicate.
Implications for Human Health
These resistance mechanisms have significant consequences for human health. Treatment failures for common and life-threatening fungal infections like candidiasis and aspergillosis are becoming more frequent. When a first-line drug is ineffective, clinicians must use alternative treatments that may be more toxic or less effective, leading to prolonged illness and higher mortality rates.
The challenge is amplified by multidrug-resistant fungal pathogens, sometimes called “superbugs.” A prominent example is Candida auris, a yeast that can resist multiple classes of antifungal drugs at once. This pathogen can use several resistance strategies, including target site alterations and efflux pump overexpression, making infections extremely difficult to manage.
The rise of resilient fungi is a threat to individuals with weakened immune systems, such as cancer patients or organ transplant recipients. These patients are more susceptible to invasive fungal infections, and treatment failure can have severe outcomes. The spread of resistant fungi in healthcare settings is also a concern, as it can lead to outbreaks that are difficult to contain.