Functional Assessment of 2,177 U.S. and International Drugs Identifies the Quinoline Nitroxoline as a Potent Amoebicidal Agent against the Pathogen Balamuthia mandrillaris

Authors

Matthew T. Laurie, University of California, San Francisco
Corin V. White, California State University, Monterey Bay
Hanna Retallack, University of California, San Francisco
Wesley Wu, University of California, San Francisco
Matthew S. Moser, University of California, San Francisco
Judy A. Sakanari, University of California, San Francisco
Kenny Ang, University of California, San Francisco
Christopher Wilson, University of California, San Francisco
Michelle R. Arkin, University of California, San Francisco
Joseph L. DeRisi, University of California, San Francisco

Document Type

Article

Publication Date

10-30-2018

Publication Title

mBio

Abstract

Balamuthia mandrillaris is a pathogenic free-living amoeba that causes a rare but almost always fatal infection of the central nervous system called granulomatous amoebic encephalitis (GAE). Two distinct forms of B. mandrillaris—a proliferative trophozoite form and a nonproliferative cyst form, which is highly resistant to harsh physical and chemical conditions—have been isolated from environmental samples worldwide and are both observed in infected tissue. Patients suffering from GAE are typically treated with aggressive and prolonged multidrug regimens that often include the antimicrobial agents miltefosine and pentamidine isethionate. However, survival rates remain low, and studies evaluating the susceptibility of B. mandrillaris to these compounds and other potential therapeutics are limited. To address the need for more-effective treatments, we screened 2,177 clinically approved compounds for in vitro activity against B. mandrillaris. The quinoline antibiotic nitroxoline (8-hydroxy-5-nitroquinoline), which has safely been used in humans to treat urinary tract infections, was identified as a lead compound. We show that nitroxoline inhibits both trophozoites and cysts at low micromolar concentrations, which are within a pharmacologically relevant range. We compared the in vitro efficacy of nitroxoline to that of drugs currently used in the standard of care for GAE and found that nitroxoline is the most potent and selective inhibitor of B. mandrillaris tested. Furthermore, we demonstrate that nitroxoline prevents B. mandrillaris-mediated destruction of host cells in cultured fibroblast and primary brain explant models also at pharmacologically relevant concentrations. Taken together, our findings indicate that nitroxoline is a promising candidate for repurposing as a novel treatment of B. mandrillaris infections.

Comments

Published in mBio by the American Society for Microbiology. Available via doi: 10.1128/mbio.02051-18.

This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license.

Recommended Citation

Laurie, Matthew T.; White, Corin V.; Retallack, Hanna; Wu, Wesley; Moser, Matthew S.; Sakanari, Judy A.; Ang, Kenny; Wilson, Christopher; Arkin, Michelle R.; and DeRisi, Joseph L., "Functional Assessment of 2,177 U.S. and International Drugs Identifies the Quinoline Nitroxoline as a Potent Amoebicidal Agent against the Pathogen Balamuthia mandrillaris" (2018). UROC Staff Publications and Presentations. 9.
https://digitalcommons.csumb.edu/uroc_staff/9