Repurposing With a Purpose

Cryptococcal meningitis is one of the most common mycoses in patients with HIV/AIDS. In developed countries, mortality rates due to the disease hover around 9%—in poor and underdeveloped regions, the number leaps to 70%. Many of those deaths are related to lack of access and difficulty in administering amphotericin B and  flucytosine. That is the most effective standard treatment, but it is expensive and carries serious adverse effects, including nephrotoxicity, hepatotoxicity, and bone marrow suppression. Fluconazole, also commonly used, does not effectively clear fungal burden and is associated with clinical relapse.

More antifungals are desperately needed, but it takes billions of dollars to get a drug to market, and the process is slow. Where are the new antifungals to come from?  Maybe from other drugs?

Researchers have begun mining drug compound “libraries,” searching for existing drugs that can be repurposed. The drugs have already passed all the regulatory hurdles—it is just a matter of finding which ones could be turned to a new use. The antidepressant sertraline, for instance, has been found to be a potent antifungal that works synergistically with fluconazole and is now being repurposed for cryptococcal meningitis. 

Researchers from University of Technology Sydney screened the Screen-Well Enzo library of 640 compounds for candidates that phenotypically inhibited the growth of Cryptococcus deuterogattii. The search turned up promising results for the anthelminthic agent flubendazole, as well as the L-type calcium channel blockers nifedipine, nisoldipine, and felodipine. Flubendazole was very active against all pathogenic Cryptococcus species, and, importantly, was equally effective against isolates resistant to fluconazole. Nifedipine, nisoldipine and felodipine inhibited Cryptococcus. Nisoldipine was also effective against Candida, Saccharomyces and Aspergillus.

The researchers say flubendazole may be the best starting point for treating cryptococcal disease, both for its effectiveness and because research has not found serious adverse effects from antihelminthic treatment. Flubendazole interferes with normal cell growth as early as 3 hours posttreatment and continues to render treated Cryptococcus cells unviable. However, because flubendazole is formulated to treat gastrointestinal worms, it is not yet known whether it would be able to reach therapeutic concentrations in the brain required for an antifungal effect.

Overall, their findings, the researchers say, “validates repurposing as a rapid approach for finding new agents to treat neglected infectious diseases.”

Source:
Truong M, Monahan LG, Carter DA, Charles IG. PeerJ. 2018;6: e4761.
doi: 10.7717/peerj.4761

Cryptococcal meningitis is one of the most common mycoses in patients with HIV/AIDS. In developed countries, mortality rates due to the disease hover around 9%—in poor and underdeveloped regions, the number leaps to 70%. Many of those deaths are related to lack of access and difficulty in administering amphotericin B and  flucytosine. That is the most effective standard treatment, but it is expensive and carries serious adverse effects, including nephrotoxicity, hepatotoxicity, and bone marrow suppression. Fluconazole, also commonly used, does not effectively clear fungal burden and is associated with clinical relapse.

More antifungals are desperately needed, but it takes billions of dollars to get a drug to market, and the process is slow. Where are the new antifungals to come from?  Maybe from other drugs?

Researchers have begun mining drug compound “libraries,” searching for existing drugs that can be repurposed. The drugs have already passed all the regulatory hurdles—it is just a matter of finding which ones could be turned to a new use. The antidepressant sertraline, for instance, has been found to be a potent antifungal that works synergistically with fluconazole and is now being repurposed for cryptococcal meningitis. 

Researchers from University of Technology Sydney screened the Screen-Well Enzo library of 640 compounds for candidates that phenotypically inhibited the growth of Cryptococcus deuterogattii. The search turned up promising results for the anthelminthic agent flubendazole, as well as the L-type calcium channel blockers nifedipine, nisoldipine, and felodipine. Flubendazole was very active against all pathogenic Cryptococcus species, and, importantly, was equally effective against isolates resistant to fluconazole. Nifedipine, nisoldipine and felodipine inhibited Cryptococcus. Nisoldipine was also effective against Candida, Saccharomyces and Aspergillus.

The researchers say flubendazole may be the best starting point for treating cryptococcal disease, both for its effectiveness and because research has not found serious adverse effects from antihelminthic treatment. Flubendazole interferes with normal cell growth as early as 3 hours posttreatment and continues to render treated Cryptococcus cells unviable. However, because flubendazole is formulated to treat gastrointestinal worms, it is not yet known whether it would be able to reach therapeutic concentrations in the brain required for an antifungal effect.

Overall, their findings, the researchers say, “validates repurposing as a rapid approach for finding new agents to treat neglected infectious diseases.”

Source:
Truong M, Monahan LG, Carter DA, Charles IG. PeerJ. 2018;6: e4761.
doi: 10.7717/peerj.4761

Cryptococcal meningitis is one of the most common mycoses in patients with HIV/AIDS. In developed countries, mortality rates due to the disease hover around 9%—in poor and underdeveloped regions, the number leaps to 70%. Many of those deaths are related to lack of access and difficulty in administering amphotericin B and  flucytosine. That is the most effective standard treatment, but it is expensive and carries serious adverse effects, including nephrotoxicity, hepatotoxicity, and bone marrow suppression. Fluconazole, also commonly used, does not effectively clear fungal burden and is associated with clinical relapse.

More antifungals are desperately needed, but it takes billions of dollars to get a drug to market, and the process is slow. Where are the new antifungals to come from?  Maybe from other drugs?

Researchers have begun mining drug compound “libraries,” searching for existing drugs that can be repurposed. The drugs have already passed all the regulatory hurdles—it is just a matter of finding which ones could be turned to a new use. The antidepressant sertraline, for instance, has been found to be a potent antifungal that works synergistically with fluconazole and is now being repurposed for cryptococcal meningitis. 

Researchers from University of Technology Sydney screened the Screen-Well Enzo library of 640 compounds for candidates that phenotypically inhibited the growth of Cryptococcus deuterogattii. The search turned up promising results for the anthelminthic agent flubendazole, as well as the L-type calcium channel blockers nifedipine, nisoldipine, and felodipine. Flubendazole was very active against all pathogenic Cryptococcus species, and, importantly, was equally effective against isolates resistant to fluconazole. Nifedipine, nisoldipine and felodipine inhibited Cryptococcus. Nisoldipine was also effective against Candida, Saccharomyces and Aspergillus.

The researchers say flubendazole may be the best starting point for treating cryptococcal disease, both for its effectiveness and because research has not found serious adverse effects from antihelminthic treatment. Flubendazole interferes with normal cell growth as early as 3 hours posttreatment and continues to render treated Cryptococcus cells unviable. However, because flubendazole is formulated to treat gastrointestinal worms, it is not yet known whether it would be able to reach therapeutic concentrations in the brain required for an antifungal effect.

Overall, their findings, the researchers say, “validates repurposing as a rapid approach for finding new agents to treat neglected infectious diseases.”

Source:
Truong M, Monahan LG, Carter DA, Charles IG. PeerJ. 2018;6: e4761.
doi: 10.7717/peerj.4761