Skip to main content
bioRxiv
  • Home
  • About
  • Submit
  • ALERTS / RSS
Advanced Search
New Results

Repurposing the quinoline antibiotic nitroxoline to treat infections caused by the brain-eating amoeba Balamuthia mandrillaris

Matthew T. Laurie, Corin V. White, Hanna Retallack, Wesley Wu, Matthew S. Moser, Judy Sakanari, Kenny Ang, Christopher Wilson, Michelle R. Arkin, Joseph L. DeRisi
doi: https://doi.org/10.1101/331785
Matthew T. Laurie
aDepartment of Biochemistry and Biophysics, University of California San Francisco, San Francisco, California, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Corin V. White
aDepartment of Biochemistry and Biophysics, University of California San Francisco, San Francisco, California, USA
bCalifornia State University Monteray Bay, Seaside, California, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Hanna Retallack
aDepartment of Biochemistry and Biophysics, University of California San Francisco, San Francisco, California, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Wesley Wu
aDepartment of Biochemistry and Biophysics, University of California San Francisco, San Francisco, California, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Matthew S. Moser
cDepartment of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, California, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Judy Sakanari
cDepartment of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, California, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Kenny Ang
dSmall Molecule Discovery Center, University of California San Francisco, San Francisco, California, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Christopher Wilson
dSmall Molecule Discovery Center, University of California San Francisco, San Francisco, California, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Michelle R. Arkin
dSmall Molecule Discovery Center, University of California San Francisco, San Francisco, California, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Joseph L. DeRisi
aDepartment of Biochemistry and Biophysics, University of California San Francisco, San Francisco, California, USA
eChan Zuckerburg Biohub, San Francisco, California, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • For correspondence: joe@derisilab.ucsf.edu
  • Abstract
  • Full Text
  • Info/History
  • Metrics
  • Supplementary material
  • Preview PDF
Loading

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 non-proliferative 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 multi-drug regimens often including 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, 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 physiologically relevant range. We compare the in vitro efficacy of nitroxoline to drugs currently used in the standard of care for GAE and find 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 physiologically relevant concentrations. Together, our findings indicate that nitroxoline is a promising candidate for repurposing as a novel treatment of B. mandrillaris infections.

Importance Balamuthia mandrillaris is responsible for hundreds of reported cases of amoebic encephalitis, the majority of which have been fatal. Despite being an exceptionally deadly pathogen, B. mandrillaris is understudied, leaving many open questions regarding epidemiology, diagnosis, and treatment. Due to the lack of effective drugs to fight B. mandrillaris infections, mortality rates remain high even for patients receiving intensive care. This study addresses the need for new anti-amoebic drugs using a high-throughput screening approach to identify novel B. mandrillaris inhibitors. The most promising candidate identified was the quinoline antibiotic nitroxoline, which has a long history of safe use in humans. We show that nitroxoline kills B. mandrillaris at physiologically relevant concentrations and exhibits greater potency and selectivity than drugs commonly used in the current standard of care. The findings we present demonstrate the potential of nitroxoline to be an important new tool in the treatment of life threatening B. mandrillaris infections.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
Back to top
PreviousNext
Posted June 06, 2018.
Download PDF

Supplementary Material

Email

Thank you for your interest in spreading the word about bioRxiv.

NOTE: Your email address is requested solely to identify you as the sender of this article.

Enter multiple addresses on separate lines or separate them with commas.
Repurposing the quinoline antibiotic nitroxoline to treat infections caused by the brain-eating amoeba Balamuthia mandrillaris
(Your Name) has forwarded a page to you from bioRxiv
(Your Name) thought you would like to see this page from the bioRxiv website.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Share
Repurposing the quinoline antibiotic nitroxoline to treat infections caused by the brain-eating amoeba Balamuthia mandrillaris
Matthew T. Laurie, Corin V. White, Hanna Retallack, Wesley Wu, Matthew S. Moser, Judy Sakanari, Kenny Ang, Christopher Wilson, Michelle R. Arkin, Joseph L. DeRisi
bioRxiv 331785; doi: https://doi.org/10.1101/331785
Digg logo Reddit logo Twitter logo Facebook logo Google logo LinkedIn logo Mendeley logo
Citation Tools
Repurposing the quinoline antibiotic nitroxoline to treat infections caused by the brain-eating amoeba Balamuthia mandrillaris
Matthew T. Laurie, Corin V. White, Hanna Retallack, Wesley Wu, Matthew S. Moser, Judy Sakanari, Kenny Ang, Christopher Wilson, Michelle R. Arkin, Joseph L. DeRisi
bioRxiv 331785; doi: https://doi.org/10.1101/331785

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
  • Tweet Widget
  • Facebook Like
  • Google Plus One

Subject Area

  • Pharmacology and Toxicology
Subject Areas
All Articles
  • Animal Behavior and Cognition (3585)
  • Biochemistry (7539)
  • Bioengineering (5494)
  • Bioinformatics (20724)
  • Biophysics (10292)
  • Cancer Biology (7946)
  • Cell Biology (11609)
  • Clinical Trials (138)
  • Developmental Biology (6584)
  • Ecology (10161)
  • Epidemiology (2065)
  • Evolutionary Biology (13573)
  • Genetics (9511)
  • Genomics (12811)
  • Immunology (7900)
  • Microbiology (19490)
  • Molecular Biology (7632)
  • Neuroscience (41969)
  • Paleontology (307)
  • Pathology (1254)
  • Pharmacology and Toxicology (2189)
  • Physiology (3258)
  • Plant Biology (7017)
  • Scientific Communication and Education (1293)
  • Synthetic Biology (1946)
  • Systems Biology (5417)
  • Zoology (1112)