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

Nature Microbiology volume 2, pages 1403–1414 (2017)Cite this article

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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.

Malaria remains a global health calamity, with an estimated 212 million cases and 429,000 deaths1 in 2015, that occurs mostly in sub-Saharan Africa and results from infection with the Apicomplexan parasite Plasmodium falciparum (Pf). Improved malaria treatment and control has reduced morbidity and mortality worldwide by 40–50% since 2000 (ref. 1), due largely to highly effective artemisinin-based combination therapies and mosquito vector control measures1,2. An important strategy to further advance the malaria elimination agenda is to include transmission-blocking agents in combination therapies3. Such agents inhibit the development of parasite gametocytes (GAMs), which represent an alternative form of intra-erythrocytic development to the pathogenic asexual blood stage (ABS) parasites and that mature over five stages4. Only stage V GAMS, which may survive days to weeks in circulation5, can continue the Pf lifecycle in Anopheles mosquitoes following ingestion of a parasitized blood meal. In the mosquito midgut, male GAMs exflagellate and produce microgametes that can fuse with female macrogametes to produce zygotes. Following subsequent development as ookinetes and oocysts, sporozoites are formed. Once inoculated in a new host, they will develop in the liver and initiate a new ABS cycle6.

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Fig. 1: Identifying HHQs as potent Pf ABS and GAM inhibitors.
Fig. 2: HHQs demonstrate potent transmission-blocking activity and inhibit male gamete exflagellation.
Fig. 3: PfMDR1 mutations associated with HHQ resistance localize to its drug-binding pocket and can sensitize parasites to first-line antimalarial drugs and the preclinical candidate ACT-451840.
Fig. 4: GNF-Pf-5660 causes a decrease in Hz and total haem iron levels in wild-type ABS Dd2-B2 and mutant HHQ-resistant PfMDR1selY290F parasites, the latter at significantly higher compound concentrations.
Fig. 5: HHQs inhibit Hb endocytosis.

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Acknowledgements

The authors thank T.T. Diagana (Novartis Institute for Tropical Diseases, Singapore) for provision of the compounds, the Red Cross (Australia and the USA) for the provision of human blood for cell cultures, and G. Stevenson for assistance with the triaging of compounds following screening. The authors acknowledge the Bill and Melinda Gates Foundation (grant OPP1040399 to D.A.F. and V.M.A. and grant OPP1054480 to E.A.W. and D.A.F.), the National Institutes of Health (grant R01 AI103058 to E.A.W. and D.A.F., grant R01 AI50234 to D.A.F, and R01 AI110329 to T.J.E.), the Australian Research Council (LP120200557 to V.M.A.) and the Medicines for Malaria Venture for their continued support. P.E.F. and M.I.V. are supported by the Northern Portugal Regional Operational Programme (NORTE 2020), under the Portugal 2020 Partnership Agreement, through the European Regional Development Fund (FEDER).

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Author notes

  1. Andrea Ruecker

    Present address: Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, OX3 7FZ, UK

Authors and Affiliations

  1. Department of Microbiology and Immunology, Columbia University Medical Center, New York, NY, 10032, USA

    Manu Vanaerschot, T. R. Santha Kumar, Kelly Rubiano, Sonia Gulati, Philipp P. Henrich, Caroline L. Ng, James M. Murithi, Ori J. Lieberman & David A. Fidock

  2. Discovery Biology, Griffith Institute for Drug Discovery, Griffith University, Nathan, 4111, Queensland, Australia

    Leonardo Lucantoni, Sandra Duffy & Vicky M. Avery

  3. Sanaria Inc., Rockville, MD, 20852, USA

    Tao Li, Kim Lee Sim & Stephen L. Hoffman

  4. Division of Pharmacology, Department of Medicine, University of Cape Town, Cape Town, 7925, South Africa

    Jill M. Combrinck

  5. Department of Life Sciences, Imperial College, London, SW7 2AZ, UK

    Andrea Ruecker, Robert E. Sinden & Michael J. Delves

  6. Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, 4710-057, Braga, Portugal

    Pedro E. Ferreira & M. Isabel Veiga

  7. Dipartimento di Malattie Infettive, Parassitarie ed Immunomediate, Istituto Superiore di Sanità, 00161, Rome, Italy

    Giulia Siciliano & Pietro Alano

  8. University of California, San Diego, School of Medicine, La Jolla, CA, 92093, USA

    Victoria C. Corey & Elizabeth A. Winzeler

  9. Department of Chemistry, University of Cape Town, Cape Town, 7700, South Africa

    Timothy J. Egan

  10. Division of Infectious Diseases, Department of Medicine, Columbia University Medical Center, New York, NY, 10032, USA

    David A. Fidock

  11. Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, 10400, Thailand

    Andrea Ruecker

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Contributions

L.L. and S.D. screened the Novartis-GNF Malaria Box against early- and late-stage GAMs using LUC or GFP-imaging technologies, assayed ABS parasites and mammalian cells and confirmed compound potency. L.L., S.D. and V.M.A. analysed screening data and selected the HHQs for further evaluation. T.L., K.L.S. and S.L.H. contributed in vitro membrane feeding and male gametocyte exflagellation assay data. A.R., R.E.S. and M.D. contributed the DGFA data. M.V. and T.R.S.K. performed in vivo efficacy studies. K.R., M.V. and T.R.S.K. performed in vivo transmission-blocking studies. S.G. performed selections for HHQ-resistant lines, which were cloned by O.L. and M.V. Whole-genome sequence analysis was performed by V.C.C., P.P.H. and E.A.W. Gene editing of pfmdr1 was performed by M.V. with help from C.L.N. and D.A.F. Susceptibility assays on resistant lines with clinical and experimental antimalarials were performed by M.V. with help from J.M.M. Early- and late-stage GAM susceptibility testing was performed by G.S. and P.A. Haem fractionation data were provided by J.M.C. and T.J.E. PfMDR1 modelling studies were performed by P.E.F and M.I.V. Data were compiled by M.V., L.L. and D.A.F., who wrote the manuscript with input from V.M.A. All authors approved of the final version.

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Correspondence to David A. Fidock.

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Vanaerschot, M., Lucantoni, L., Li, T. et al. Hexahydroquinolines are antimalarial candidates with potent blood-stage and transmission-blocking activity. Nat Microbiol 2, 1403–1414 (2017). https://doi.org/10.1038/s41564-017-0007-4

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