期刊
JOURNAL OF INFECTIOUS DISEASES
卷 219, 期 7, 页码 1095-1103出版社
OXFORD UNIV PRESS INC
DOI: 10.1093/infdis/jiy622
关键词
Naegleria fowleri; phenotypic screen; drug discovery; posaconazole; azithromycin; miltefosine; primary amoebic meningoencephalitis
资金
- National Institute of Allergy and Infectious Diseases [R21AI103664, R21AI119787]
- University of South Florida, College of Public Health
- Georgia Research Alliance
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 mu M). 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.
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