Phenotypic screens reveal posaconazole as a rapidly acting amebicidal combination partner for treatment of primary amoebic meningoencephalitis

Beatrice L. Colon; Christopher A. Rice; R. Kiplin Guy; Dennis E. Kyle

doi:10.1093/infdis/jiy622

Phenotypic screens reveal posaconazole as a rapidly acting amebicidal combination partner for treatment of primary amoebic meningoencephalitis

Beatrice L. Colon
, Christopher A. Rice
, R. Kiplin Guy
, Dennis E. Kyle

Research output: Contribution to journal › Article › peer-review

37 Scopus citations

Abstract

Naegleria fowleri is the causative agent of primary amoebic meningoencephalitis (PAM), which is fatal in >97% of cases. In this study, we aimed to identify new, rapidly acting drugs to increase survival rates. We conducted phenotypic screens of libraries of Food and Drug Administration-approved compounds and the Medicines for Malaria Venture Pathogen Box and validated 14 hits (defined as a 50% inhibitory concentration of <1 μM). The hits were then prioritized by assessing the rate of action and efficacy in combination with current drugs used to treat PAM. Posaconazole was found to inhibit amoeba growth within the first 12 hours of exposure, which was faster than any currently used drug. In addition, posaconazole cured 33% of N. fowleri-infected mice at a dose of 20 mg/kg and, in combination with azithromycin, increased survival by an additional 20%. Fluconazole, which is currently used for PAM therapy, was ineffective in vitro and vivo. Our results suggest posaconazole could replace fluconazole in the treatment of PAM.

Original language	English
Pages (from-to)	1095-1103
Number of pages	9
Journal	Journal of Infectious Diseases
Volume	219
Issue number	7
DOIs	https://doi.org/10.1093/infdis/jiy622
State	Published - Mar 15 2019

Bibliographical note

Publisher Copyright:
© The Author(s) 2018. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved.

Funding

This work was supported by the National Institute of Allergy and Infectious Diseases (R21AI103664 and R21AI119787), the University of South Florida, College of Public Health, and the Georgia Research Alliance. Financial support. This work was supported by the National Institute of Allergy and Infectious Diseases (R21AI103664 and R21AI119787), the University of South Florida, College of Public Health, and the Georgia Research Alliance.

Funders	Funder number
Georgia Research Alliance
National Institute of Allergy and Infectious F32-AI286447 Cydney N. Johnson Diseases National Institute of Allergy and Infectious R01AI168214 Jason W. Rosch Diseases National Institute of Allergy and Infectious P30 Cydney N. Johnson Diseases National Institute of Allergy and Infectious R00-AI166116 Christopher D. Radka Diseases National Institute of Allergy and Infectious T32-AI106700 Cydney N. Johnson Diseases National Institute of Allergy and Infectious R01AI192221 Jason W. Rosch Diseases National Inst...	R21AI103664, R21AI119787
College of Public Health
University of South Florida

Keywords

Azithromycin
Drug discovery
Miltefosine
Naegleria fowleri
Phenotypic screen
Posaconazole
Primary amoebic meningo encephalitis

ASJC Scopus subject areas

Immunology and Allergy
Infectious Diseases

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1093/infdis/jiy622

Cite this

@article{18e1cfc867e94b75ae1ac479e1531ca5,

title = "Phenotypic screens reveal posaconazole as a rapidly acting amebicidal combination partner for treatment of primary amoebic meningoencephalitis",

abstract = "Naegleria fowleri is the causative agent of primary amoebic meningoencephalitis (PAM), which is fatal in >97\% of cases. In this study, we aimed to identify new, rapidly acting drugs to increase survival rates. We conducted phenotypic screens of libraries of Food and Drug Administration-approved compounds and the Medicines for Malaria Venture Pathogen Box and validated 14 hits (defined as a 50\% inhibitory concentration of <1 μM). The hits were then prioritized by assessing the rate of action and efficacy in combination with current drugs used to treat PAM. Posaconazole was found to inhibit amoeba growth within the first 12 hours of exposure, which was faster than any currently used drug. In addition, posaconazole cured 33\% of N. fowleri-infected mice at a dose of 20 mg/kg and, in combination with azithromycin, increased survival by an additional 20\%. Fluconazole, which is currently used for PAM therapy, was ineffective in vitro and vivo. Our results suggest posaconazole could replace fluconazole in the treatment of PAM.",

keywords = "Azithromycin, Drug discovery, Miltefosine, Naegleria fowleri, Phenotypic screen, Posaconazole, Primary amoebic meningo encephalitis",

author = "Colon, \{Beatrice L.\} and Rice, \{Christopher A.\} and Guy, \{R. Kiplin\} and Kyle, \{Dennis E.\}",

year = "2019",

month = mar,

day = "15",

doi = "10.1093/infdis/jiy622",

language = "English",

volume = "219",

pages = "1095--1103",

number = "7",

}

TY - JOUR

T1 - Phenotypic screens reveal posaconazole as a rapidly acting amebicidal combination partner for treatment of primary amoebic meningoencephalitis

AU - Colon, Beatrice L.

AU - Rice, Christopher A.

AU - Guy, R. Kiplin

AU - Kyle, Dennis E.

PY - 2019/3/15

Y1 - 2019/3/15

N2 - Naegleria fowleri is the causative agent of primary amoebic meningoencephalitis (PAM), which is fatal in >97% of cases. In this study, we aimed to identify new, rapidly acting drugs to increase survival rates. We conducted phenotypic screens of libraries of Food and Drug Administration-approved compounds and the Medicines for Malaria Venture Pathogen Box and validated 14 hits (defined as a 50% inhibitory concentration of <1 μM). The hits were then prioritized by assessing the rate of action and efficacy in combination with current drugs used to treat PAM. Posaconazole was found to inhibit amoeba growth within the first 12 hours of exposure, which was faster than any currently used drug. In addition, posaconazole cured 33% of N. fowleri-infected mice at a dose of 20 mg/kg and, in combination with azithromycin, increased survival by an additional 20%. Fluconazole, which is currently used for PAM therapy, was ineffective in vitro and vivo. Our results suggest posaconazole could replace fluconazole in the treatment of PAM.

AB - Naegleria fowleri is the causative agent of primary amoebic meningoencephalitis (PAM), which is fatal in >97% of cases. In this study, we aimed to identify new, rapidly acting drugs to increase survival rates. We conducted phenotypic screens of libraries of Food and Drug Administration-approved compounds and the Medicines for Malaria Venture Pathogen Box and validated 14 hits (defined as a 50% inhibitory concentration of <1 μM). The hits were then prioritized by assessing the rate of action and efficacy in combination with current drugs used to treat PAM. Posaconazole was found to inhibit amoeba growth within the first 12 hours of exposure, which was faster than any currently used drug. In addition, posaconazole cured 33% of N. fowleri-infected mice at a dose of 20 mg/kg and, in combination with azithromycin, increased survival by an additional 20%. Fluconazole, which is currently used for PAM therapy, was ineffective in vitro and vivo. Our results suggest posaconazole could replace fluconazole in the treatment of PAM.

KW - Azithromycin

KW - Drug discovery

KW - Miltefosine

KW - Naegleria fowleri

KW - Phenotypic screen

KW - Posaconazole

KW - Primary amoebic meningo encephalitis

UR - https://www.scopus.com/pages/publications/85063014448

UR - https://www.scopus.com/pages/publications/85063014448#tab=citedBy

U2 - 10.1093/infdis/jiy622

DO - 10.1093/infdis/jiy622

M3 - Article

C2 - 30358879

AN - SCOPUS:85063014448

SN - 0022-1899

VL - 219

SP - 1095

EP - 1103

JO - Journal of Infectious Diseases

JF - Journal of Infectious Diseases

IS - 7

ER -

Phenotypic screens reveal posaconazole as a rapidly acting amebicidal combination partner for treatment of primary amoebic meningoencephalitis

Abstract

Bibliographical note

Funding

Keywords

ASJC Scopus subject areas

UN SDGs

Access to Document

Other files and links

Fingerprint

Cite this