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

    Author(s)
    Vanaerschot, Manu
    Lucantoni, Leonardo
    Li, Tao
    Combrinck, Jill M
    Ruecker, Andrea
    Kumar, TR 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
    Sim, Kim Lee
    Winzeler, Elizabeth A
    Egan, Timothy J
    Hoffman, Stephen L
    Avery, Vicky M
    Fidock, David A
    Griffith University Author(s)
    Duffy, Sandra
    Avery, Vicky M.
    Year published
    2017
    Metadata
    Show full item record
    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 ...
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    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.
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    Journal Title
    Nature Microbiology
    Volume
    2
    DOI
    https://doi.org/10.1038/s41564-017-0007-4
    Subject
    Microbiology
    Microbiology not elsewhere classified
    Medical microbiology
    Publication URI
    http://hdl.handle.net/10072/370071
    Collection
    • Journal articles

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