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Title: Hexahydroquinolines are antimalarial candidates with potent blood-stage and transmission-blocking activity
Authors: Manu Vanaerschot
Leonardo Lucantoni
Tao Li
Jill M. Combrinck
Andrea Ruecker
T. R.Santha Kumar
Kelly Rubiano
Pedro E. Ferreira
Giulia Siciliano
Sonia Gulati
Philipp P. Henrich
Caroline L. Ng
James M. Murithi
Victoria C. Corey
Sandra Duffy
Ori J. Lieberman
M. Isabel Veiga
Robert E. Sinden
Pietro Alano
Michael J. Delves
Kim Lee Sim
Elizabeth A. Winzeler
Timothy J. Egan
Stephen L. Hoffman
Vicky M. Avery
David A. Fidock
Columbia University Medical Center
Griffith University
Sanaria Inc.
University of Cape Town
Imperial College London
Universidade do Minho, Escola de Ciências da Saúde
Istituto Superiore Di Sanita
University of California, San Diego, School of Medicine
Mahidol University
Nuffield Department of Clinical Medicine
Keywords: Biochemistry, Genetics and Molecular Biology;Immunology and Microbiology
Issue Date: 1-Oct-2017
Citation: Nature Microbiology. Vol.2, No.10 (2017), 1403-1414
Abstract: © 2017 The Author(s). Antimalarial compounds with dual therapeutic and transmission-blocking activity are desired as high-value partners for combination therapies. Here, we report the identification and characterization of hexahydroquinolines (HHQs) that show low nanomolar potency against both pathogenic and transmissible intra-erythrocytic forms of the malaria parasite Plasmodium falciparum. This activity translates into potent transmission-blocking potential, as shown by in vitro male gamete formation assays and reduced oocyst infection and prevalence in Anopheles mosquitoes. In vivo studies illustrated the ability of lead HHQs to suppress Plasmodium berghei blood-stage parasite proliferation. Resistance selection studies, confirmed by CRISPR-Cas9-based gene editing, identified the digestive vacuole membrane-spanning transporter PfMDR1 (P. falciparum multidrug resistance gene-1) as a determinant of parasite resistance to HHQs. Haemoglobin and haem fractionation assays suggest a mode of action that results in reduced haemozoin levels and might involve inhibition of host haemoglobin uptake into intra-erythrocytic parasites. Furthermore, parasites resistant to HHQs displayed increased susceptibility to several first-line antimalarial drugs, including lumefantrine, confirming that HHQs have a different mode of action to other antimalarials drugs for which PfMDR1 is known to confer resistance. This work evokes therapeutic strategies that combine opposing selective pressures on this parasite transporter as an approach to countering the emergence and transmission of multidrug-resistant P. falciparum malaria.
ISSN: 20585276
Appears in Collections:Scopus 2016-2017

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