Publication:
Hexahydroquinolines are antimalarial candidates with potent blood-stage and transmission-blocking activity

Issued Date

2017-10-01

Resource Type

Article

ISSN

20585276

DOI

10.1038/s41564-017-0007-4

Other identifier(s)

2-s2.0-85029150535

Rights

Mahidol University

Rights Holder(s)

SCOPUS

Bibliographic Citation

Nature Microbiology. Vol.2, No.10 (2017), 1403-1414

Suggested Citation

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 Hexahydroquinolines are antimalarial candidates with potent blood-stage and transmission-blocking activity. Nature Microbiology. Vol.2, No.10 (2017), 1403-1414. doi:10.1038/s41564-017-0007-4 Retrieved from: https://repository.li.mahidol.ac.th/handle/123456789/41813

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Title

Hexahydroquinolines are antimalarial candidates with potent blood-stage and transmission-blocking activity

Author(s)

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

Other Contributor(s)

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

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.

Keyword(s)

Biochemistry, Genetics and Molecular Biology
 Immunology and Microbiology

Availability

URI

https://repository.li.mahidol.ac.th/handle/123456789/41813

Collections

Scopus 2016-2017