Invasive fungal infections cause 1.6 million deaths annually, primarily in immunocompromised individuals. Mortality rates are as high as 90% due to limited treatments. The azole class antifungal, fluconazole, is widely available and has multi-species activity but only inhibits growth instead of killing fungal cells, necessitating long treatments. To improve treatment, we used our novel high-throughput method, the overlap2 method (O2M) to identify drugs that interact with fluconazole, either increasing or decreasing efficacy. We identified 40 molecules that act synergistically (amplify activity) and 19 molecules that act antagonistically (decrease efficacy) when combined with fluconazole. We found that critical frontline beta-lactam antibiotics antagonize fluconazole activity. A promising fluconazole-synergizing anticholinergic drug, dicyclomine, increases fungal cell permeability and inhibits nutrient intake when combined with fluconazole. In vivo, this combination doubled the time-to-endpoint of mice with Cryptococcus neoformans meningitis. Thus, our ability to rapidly identify synergistic and antagonistic drug interactions can potentially alter the patient outcomes.
Keywords: Cryptococcus neoformans; drug combination; drug discovery; fungal infection; genetics; genomics; infectious disease; microbiology.
Individuals with weakened immune systems – such as recipients of organ transplants – can fall prey to illnesses caused by fungi that are harmless to most people. These infections are difficult to manage because few treatments exist to fight fungi, and many have severe side effects. Antifungal drugs usually slow the growth of fungi cells rather than kill them, which means that patients must remain under treatment for a long time, or even for life. One way to boost efficiency and combat resistant infections is to combine antifungal treatments with drugs that work in complementary ways: the drugs strengthen each other’s actions, and together they can potentially kill the fungus rather than slow its progression. However, not all drug combinations are helpful. In fact, certain drugs may interact in ways that make treatment less effective. This is particularly concerning because people with weakened immune systems often take many types of medications. Here, Wambaugh et al. harnessed a new high-throughput system to screen how 2,000 drugs (many of which already approved to treat other conditions) affected the efficiency of a common antifungal called fluconazole. This highlighted 19 drugs that made fluconazole less effective, some being antibiotics routinely used to treat patients with weakened immune systems. On the other hand, 40 drugs boosted the efficiency of fluconazole, including dicyclomine, a compound currently used to treat inflammatory bowel syndrome. In fact, pairing dicyclomine and fluconazole more than doubled the survival rate of mice with severe fungal infections. The combined treatment could target many species of harmful fungi, even those that had become resistant to fluconazole alone. The results by Wambaugh et al. point towards better treatments for individuals with serious fungal infections. Drugs already in circulation for other conditions could be used to boost the efficiency of fluconazole, while antibiotics that do not decrease the efficiency of this medication should be selected to treat at-risk patients.
© 2020, Wambaugh et al.