Cryptococcus species are a clinically important group of opportunistic fungal pathogens that can cause life threatening disease, particularly in the immunocompromised patient population. Historically, this has involved patients with advanced HIV, but is becoming more prevalent in other immunovulnerable populations. The primary pathogens, C. neoformans and C. gattii, are ubiquitous in the environment which provides ample opportunity to establish primary pulmonary infections upon inhalation of the corresponding spore or yeast. Unfortunately, many cases of pulmonary cryptococcosis can progress and lead to deadly disseminated fungal infections. Of special importance is the strong preference (~90%) for the pathogen to establish infection within the central nervous system, especially through infection of the meninges leading to cryptococcal meningitis. This is the leading causeof meningitis world-wide and is associated with a very high mortality rate (~80%). Treatment of cryptococcal infections is difficult owing to the limited number of effective treatment options available. The difficulty of many antifungal drugs to effectively traverse the blood-brain barrier and reach therapeutically relevant concentration within the CNS limits current treatment options to just three agents: fluconazole, 5-flucytosine and amphotericin. The evolution of substantial levels of resistance to fluconazole and 5-flucytosine in circulating strains of Cryptococcus has significantly undermined these agents while the toxicities associates with amphotericin are a well-known problem. Based on the limited options for treating these life-threatening infections, there is a compelling need to develop more effective agents capable of reaching the CNS. QMD is developing antifungal antifolates that inhibit the essential enzyme dihydrofolate reductase (DHFR). Although DHFR is a clinicallyvalidated target in several eukaryotic pathogens such as Plasmodium falciparum and Toxoplasma gondii, the efforts to exploit this target for antifungal drug development has lagged far behind. QMD has identified a novelinhibitor against Cryptococcus that is characterized by high levels of antifungal activity while initial dose-tolerance and pharmacokinetic studies suggest the compound has a favorable profile to demonstrate in vivo efficacy in animal models of infection. In this Phase I application, we will work to advance this program for the treatment of cryptococcal infections by (1) antimicrobial profiling, PK/PD studies and elucidation of mechanism(s) of resistance, (2) exploring structural modifications to increase the selectivity index over the host enzyme, and (3)evaluation of lead and back-up compounds in murine models of infection. Successful demonstration in proof-of-concept in vivo efficacy will enable us to further advance these antifungal candidates toward clinical application.
Public Health Relevance Statement: Narrative: Infections produced by the fungal pathogen Cryptococcus neoformans are a significant cause of mortality in the immune suppressed population and are difficult to treat owing to CNS involvement and drug resistance. QMD is developing a new therapeutic candidate that inhibits an important metabolic pathway in this organism.
Project Terms: <5-FC><5-Fluorocytosine>
