Combining Stage Specificity and Metabolomic Profiling to Advance Antimalarial Drug Discovery.

Autor:	Murithi JM; Department of Microbiology and Immunology, Columbia University Irving Medical Center, New York, NY 10032, USA., Owen ES; Department of Biochemistry and Molecular Biology, Pennsylvania State University, University Park, PA 16802, USA., Istvan ES; Department of Medicine, Division of Infectious Diseases, and Department of Molecular Microbiology, Washington University School of Medicine, Saint Louis MO 63130, USA., Lee MCS; Parasites and Microbes Programme, Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridgeshire CB10 1SA, UK., Ottilie S; School of Medicine, University of California San Diego (UCSD), La Jolla, CA 92093, USA., Chibale K; Drug Discovery and Development Centre (H3D), University of Cape Town, Rondebosch 7701, South Africa; South African Medical Research Council Drug Discovery and Development Research Unit, Department of Chemistry & Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Rondebosch 7701, South Africa., Goldberg DE; Department of Medicine, Division of Infectious Diseases, and Department of Molecular Microbiology, Washington University School of Medicine, Saint Louis MO 63130, USA., Winzeler EA; School of Medicine, University of California San Diego (UCSD), La Jolla, CA 92093, USA., Llinás M; Department of Biochemistry and Molecular Biology, Pennsylvania State University, University Park, PA 16802, USA; Department of Chemistry, Pennsylvania State University, University Park, PA 16802, USA; Huck Center for Malaria Research, Pennsylvania State University, University Park, PA 16802, USA., Fidock DA; Department of Microbiology and Immunology, Columbia University Irving Medical Center, New York, NY 10032, USA; Division of Infectious Diseases, Department of Medicine, Columbia University Irving Medical Center, New York, NY 10032, USA. Electronic address: df2260@cumc.columbia.edu., Vanaerschot M; Department of Microbiology and Immunology, Columbia University Irving Medical Center, New York, NY 10032, USA. Electronic address: manu.vanaerschot@gmail.com.
Jazyk:	angličtina
Zdroj:	Cell chemical biology [Cell Chem Biol] 2020 Feb 20; Vol. 27 (2), pp. 158-171.e3. Date of Electronic Publication: 2019 Dec 05.
DOI:	10.1016/j.chembiol.2019.11.009
Abstrakt:	We report detailed susceptibility profiling of asexual blood stages of the malaria parasite Plasmodium falciparum to clinical and experimental antimalarials, combined with metabolomic fingerprinting. Results revealed a variety of stage-specific and metabolic profiles that differentiated the modes of action of clinical antimalarials including chloroquine, piperaquine, lumefantrine, and mefloquine, and identified late trophozoite-specific peak activity and stage-specific biphasic dose-responses for the mitochondrial inhibitors DSM265 and atovaquone. We also identified experimental antimalarials hitting previously unexplored druggable pathways as reflected by their unique stage specificity and/or metabolic profiles. These included several ring-active compounds, ones affecting hemoglobin catabolism through distinct pathways, and mitochondrial inhibitors with lower propensities for resistance than either DSM265 or atovaquone. This approach, also applicable to other microbes that undergo multiple differentiation steps, provides an effective tool to prioritize compounds for further development within the context of combination therapies. Competing Interests: Declaration of Interests The authors declare no competing interests. (Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.)
Databáze:	MEDLINE
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