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

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. DelvesKim Lee Sim, Elizabeth A. Winzeler, Timothy J. Egan, Stephen L. Hoffman, Vicky M. Avery, David A. Fidock

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)1403-1414
Number of pages12
JournalNature Microbiology
Volume2
Issue number10
DOIs
Publication statusPublished - Oct 1 2017

Fingerprint

Antimalarials
Parasites
MDR Genes
Falciparum Malaria
Plasmodium falciparum
Hemoglobins
Clustered Regularly Interspaced Short Palindromic Repeats
Plasmodium berghei
Anopheles
Membrane Transport Proteins
Oocysts
Vacuoles
Culicidae
Heme
Germ Cells
Therapeutics
Infection

ASJC Scopus subject areas

  • Microbiology
  • Immunology
  • Applied Microbiology and Biotechnology
  • Genetics
  • Microbiology (medical)
  • Cell Biology

Cite this

Vanaerschot, M., Lucantoni, L., Li, T., Combrinck, J. M., Ruecker, A., Kumar, T. R. S., ... Fidock, D. A. (2017). Hexahydroquinolines are antimalarial candidates with potent blood-stage and transmission-blocking activity. Nature Microbiology, 2(10), 1403-1414. https://doi.org/10.1038/s41564-017-0007-4

Hexahydroquinolines are antimalarial candidates with potent blood-stage and transmission-blocking activity. / Vanaerschot, Manu; Lucantoni, Leonardo; Li, Tao; Combrinck, Jill M.; Ruecker, Andrea; Kumar, T. R.Santha; Rubiano, Kelly; Ferreira, Pedro E.; Siciliano, Giulia; Gulati, Sonia; Henrich, Philipp P.; Ng, Caroline L.; Murithi, James M.; Corey, Victoria C.; Duffy, Sandra; Lieberman, Ori J.; Veiga, M. Isabel; Sinden, Robert E.; Alano, Pietro; Delves, Michael J.; Lee Sim, Kim; Winzeler, Elizabeth A.; Egan, Timothy J.; Hoffman, Stephen L.; Avery, Vicky M.; Fidock, David A.

In: Nature Microbiology, Vol. 2, No. 10, 01.10.2017, p. 1403-1414.

Research output: Contribution to journalArticle

Vanaerschot, M, Lucantoni, L, Li, T, Combrinck, JM, Ruecker, A, Kumar, TRS, Rubiano, K, Ferreira, PE, Siciliano, G, Gulati, S, Henrich, PP, Ng, CL, Murithi, JM, Corey, VC, Duffy, S, Lieberman, OJ, Veiga, MI, Sinden, RE, Alano, P, Delves, MJ, Lee Sim, K, Winzeler, EA, Egan, TJ, Hoffman, SL, Avery, VM & Fidock, DA 2017, 'Hexahydroquinolines are antimalarial candidates with potent blood-stage and transmission-blocking activity', Nature Microbiology, vol. 2, no. 10, pp. 1403-1414. https://doi.org/10.1038/s41564-017-0007-4
Vanaerschot, Manu ; Lucantoni, Leonardo ; Li, Tao ; Combrinck, Jill M. ; Ruecker, Andrea ; Kumar, T. R.Santha ; Rubiano, Kelly ; Ferreira, Pedro E. ; Siciliano, Giulia ; Gulati, Sonia ; Henrich, Philipp P. ; Ng, Caroline L. ; Murithi, James M. ; Corey, Victoria C. ; Duffy, Sandra ; Lieberman, Ori J. ; Veiga, M. Isabel ; Sinden, Robert E. ; Alano, Pietro ; Delves, Michael J. ; Lee Sim, Kim ; Winzeler, Elizabeth A. ; Egan, Timothy J. ; Hoffman, Stephen L. ; Avery, Vicky M. ; Fidock, David A. / Hexahydroquinolines are antimalarial candidates with potent blood-stage and transmission-blocking activity. In: Nature Microbiology. 2017 ; Vol. 2, No. 10. pp. 1403-1414.
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