Repurposing drugs to fast-track therapeutic agents for the treatment of cryptococcosis

Truong, M; Monahan, LG; Carter, DA; Charles, IG

Repurposing drugs to fast-track therapeutic agents for the treatment of cryptococcosis

Truong, M Monahan, LG

Carter, DA Charles, IG

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Publication Type:: Journal Article
Citation:: PeerJ, 2018, 2018 (5)
Issue Date:: 2018-01-01

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Field	Value	Language
dc.contributor.author	Truong, M	en_US
dc.contributor.author	Monahan, LG https://orcid.org/0000-0003-2933-9000	en_US
dc.contributor.author	Carter, DA	en_US
dc.contributor.author	Charles, IG https://orcid.org/0000-0002-2423-1167	en_US
dc.date.available	2018-04-21	en_US
dc.date.issued	2018-01-01	en_US
dc.identifier.citation	PeerJ, 2018, 2018 (5)	en_US
dc.identifier.uri	http://hdl.handle.net/10453/126532
dc.description.abstract	© 2018 Truong et al. Many infectious diseases disproportionately affect people in the developing world. Cryptococcal meningitis is one of the most common mycoses in HIV-AIDS patients, with the highest burden of disease in sub-Saharan Africa. Current best treatment regimens still result in unacceptably high mortality rates, and more effective antifungal agents are needed urgently. Drug development is hampered by the difficulty of developing effective antifungal agents that are not also toxic to human cells, and by a reluctance among pharmaceutical companies to invest in drugs that cannot guarantee a high financial return. Drug repurposing, where existing drugs are screened for alternative activities, is becoming an attractive approach in antimicrobial discovery programs, and various compound libraries are now commercially available. As these drugs have already undergone extensive optimisation and passed regulatory hurdles this can fast-track their progress to market for new uses. This study screened the Screen-Well Enzo library of 640 compounds for candidates that phenotypically inhibited the growth of Cryptococcus deuterogattii. The anthelminthic agent flubendazole, and L-type calcium channel blockers nifedipine, nisoldipine and felodipine, appeared particularly promising and were tested in additional strains and species. Flubendazole was very active against all pathogenic Cryptococcus species, with minimum inhibitory concentrations of 0.039-0.156 μg/mL, and was equally effective against isolates that were resistant to fluconazole. While nifedipine, nisoldipine and felodipine all inhibited Cryptococcus, nisoldipine was also effective against Candida, Saccharomyces and Aspergillus. This study validates repurposing as a rapid approach for finding new agents to treat neglected infectious diseases.	en_US
dc.relation.ispartof	PeerJ	en_US
dc.relation.isbasedon	10.7717/peerj.4761	en_US
dc.title	Repurposing drugs to fast-track therapeutic agents for the treatment of cryptococcosis	en_US
dc.type	Journal Article
utslib.citation.volume	5	en_US
utslib.citation.volume	2018	en_US
utslib.for	0605 Microbiology	en_US
utslib.for	1115 Pharmacology and Pharmaceutical Sciences	en_US
utslib.for	06 Biological Sciences	en_US
utslib.for	11 Medical and Health Sciences	en_US
pubs.embargo.period	Not known	en_US
pubs.organisational-group	/University of Technology Sydney
pubs.organisational-group	/University of Technology Sydney/Faculty of Science
pubs.organisational-group	/University of Technology Sydney/Strength - ithree - Institute of Infection, Immunity and Innovation
utslib.copyright.status	open_access
pubs.issue	5	en_US
pubs.publication-status	Published	en_US
pubs.volume	2018	en_US

Abstract:

© 2018 Truong et al. Many infectious diseases disproportionately affect people in the developing world. Cryptococcal meningitis is one of the most common mycoses in HIV-AIDS patients, with the highest burden of disease in sub-Saharan Africa. Current best treatment regimens still result in unacceptably high mortality rates, and more effective antifungal agents are needed urgently. Drug development is hampered by the difficulty of developing effective antifungal agents that are not also toxic to human cells, and by a reluctance among pharmaceutical companies to invest in drugs that cannot guarantee a high financial return. Drug repurposing, where existing drugs are screened for alternative activities, is becoming an attractive approach in antimicrobial discovery programs, and various compound libraries are now commercially available. As these drugs have already undergone extensive optimisation and passed regulatory hurdles this can fast-track their progress to market for new uses. This study screened the Screen-Well Enzo library of 640 compounds for candidates that phenotypically inhibited the growth of Cryptococcus deuterogattii. The anthelminthic agent flubendazole, and L-type calcium channel blockers nifedipine, nisoldipine and felodipine, appeared particularly promising and were tested in additional strains and species. Flubendazole was very active against all pathogenic Cryptococcus species, with minimum inhibitory concentrations of 0.039-0.156 μg/mL, and was equally effective against isolates that were resistant to fluconazole. While nifedipine, nisoldipine and felodipine all inhibited Cryptococcus, nisoldipine was also effective against Candida, Saccharomyces and Aspergillus. This study validates repurposing as a rapid approach for finding new agents to treat neglected infectious diseases.

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http://hdl.handle.net/10453/126532