Inhibition of Cytochrome bc1 as a Strategy for Single-Dose, Multi-Stage Antimalarial Therapy

Allison M. Stickles Departments of Physiology and Pharmacology, Molecular Microbiology and Immunology, Oregon Health and Science University, Portland, Oregon; Departments of Medicine, Pathology, and Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York; Department of Microbiology and Immunology, Drexel University College of Medicine, Philadelphia, Pennsylvania; VA Medical Center, Portland, Oregon

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Li-Min Ting Departments of Physiology and Pharmacology, Molecular Microbiology and Immunology, Oregon Health and Science University, Portland, Oregon; Departments of Medicine, Pathology, and Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York; Department of Microbiology and Immunology, Drexel University College of Medicine, Philadelphia, Pennsylvania; VA Medical Center, Portland, Oregon

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Joanne M. Morrisey Departments of Physiology and Pharmacology, Molecular Microbiology and Immunology, Oregon Health and Science University, Portland, Oregon; Departments of Medicine, Pathology, and Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York; Department of Microbiology and Immunology, Drexel University College of Medicine, Philadelphia, Pennsylvania; VA Medical Center, Portland, Oregon

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Yuexin Li Departments of Physiology and Pharmacology, Molecular Microbiology and Immunology, Oregon Health and Science University, Portland, Oregon; Departments of Medicine, Pathology, and Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York; Department of Microbiology and Immunology, Drexel University College of Medicine, Philadelphia, Pennsylvania; VA Medical Center, Portland, Oregon

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Michael W. Mather Departments of Physiology and Pharmacology, Molecular Microbiology and Immunology, Oregon Health and Science University, Portland, Oregon; Departments of Medicine, Pathology, and Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York; Department of Microbiology and Immunology, Drexel University College of Medicine, Philadelphia, Pennsylvania; VA Medical Center, Portland, Oregon

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Erin Meermeier Departments of Physiology and Pharmacology, Molecular Microbiology and Immunology, Oregon Health and Science University, Portland, Oregon; Departments of Medicine, Pathology, and Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York; Department of Microbiology and Immunology, Drexel University College of Medicine, Philadelphia, Pennsylvania; VA Medical Center, Portland, Oregon

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April M. Pershing Departments of Physiology and Pharmacology, Molecular Microbiology and Immunology, Oregon Health and Science University, Portland, Oregon; Departments of Medicine, Pathology, and Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York; Department of Microbiology and Immunology, Drexel University College of Medicine, Philadelphia, Pennsylvania; VA Medical Center, Portland, Oregon

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Isaac P. Forquer Departments of Physiology and Pharmacology, Molecular Microbiology and Immunology, Oregon Health and Science University, Portland, Oregon; Departments of Medicine, Pathology, and Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York; Department of Microbiology and Immunology, Drexel University College of Medicine, Philadelphia, Pennsylvania; VA Medical Center, Portland, Oregon

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Galen P. Miley Departments of Physiology and Pharmacology, Molecular Microbiology and Immunology, Oregon Health and Science University, Portland, Oregon; Departments of Medicine, Pathology, and Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York; Department of Microbiology and Immunology, Drexel University College of Medicine, Philadelphia, Pennsylvania; VA Medical Center, Portland, Oregon

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Sovitj Pou Departments of Physiology and Pharmacology, Molecular Microbiology and Immunology, Oregon Health and Science University, Portland, Oregon; Departments of Medicine, Pathology, and Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York; Department of Microbiology and Immunology, Drexel University College of Medicine, Philadelphia, Pennsylvania; VA Medical Center, Portland, Oregon

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Rolf W. Winter Departments of Physiology and Pharmacology, Molecular Microbiology and Immunology, Oregon Health and Science University, Portland, Oregon; Departments of Medicine, Pathology, and Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York; Department of Microbiology and Immunology, Drexel University College of Medicine, Philadelphia, Pennsylvania; VA Medical Center, Portland, Oregon

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David J. Hinrichs Departments of Physiology and Pharmacology, Molecular Microbiology and Immunology, Oregon Health and Science University, Portland, Oregon; Departments of Medicine, Pathology, and Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York; Department of Microbiology and Immunology, Drexel University College of Medicine, Philadelphia, Pennsylvania; VA Medical Center, Portland, Oregon

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Jane X. Kelly Departments of Physiology and Pharmacology, Molecular Microbiology and Immunology, Oregon Health and Science University, Portland, Oregon; Departments of Medicine, Pathology, and Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York; Department of Microbiology and Immunology, Drexel University College of Medicine, Philadelphia, Pennsylvania; VA Medical Center, Portland, Oregon

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Kami Kim Departments of Physiology and Pharmacology, Molecular Microbiology and Immunology, Oregon Health and Science University, Portland, Oregon; Departments of Medicine, Pathology, and Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York; Department of Microbiology and Immunology, Drexel University College of Medicine, Philadelphia, Pennsylvania; VA Medical Center, Portland, Oregon

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Akhil B. Vaidya Departments of Physiology and Pharmacology, Molecular Microbiology and Immunology, Oregon Health and Science University, Portland, Oregon; Departments of Medicine, Pathology, and Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York; Department of Microbiology and Immunology, Drexel University College of Medicine, Philadelphia, Pennsylvania; VA Medical Center, Portland, Oregon

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Michael K. Riscoe Departments of Physiology and Pharmacology, Molecular Microbiology and Immunology, Oregon Health and Science University, Portland, Oregon; Departments of Medicine, Pathology, and Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York; Department of Microbiology and Immunology, Drexel University College of Medicine, Philadelphia, Pennsylvania; VA Medical Center, Portland, Oregon

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Aaron Nilsen Departments of Physiology and Pharmacology, Molecular Microbiology and Immunology, Oregon Health and Science University, Portland, Oregon; Departments of Medicine, Pathology, and Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York; Department of Microbiology and Immunology, Drexel University College of Medicine, Philadelphia, Pennsylvania; VA Medical Center, Portland, Oregon

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Single-dose therapies for malaria have been proposed as a way to reduce the cost and increase the effectiveness of antimalarial treatment. However, no compound to date has shown single-dose activity against both the blood-stage Plasmodium parasites that cause disease and the liver-stage parasites that initiate malaria infection. Here, we describe a subset of cytochrome bc1 (cyt bc1) inhibitors, including the novel 4(1H)-quinolone ELQ-400, with single-dose activity against liver, blood, and transmission-stage parasites in mouse models of malaria. Although cyt bc1 inhibitors are generally classified as slow-onset antimalarials, we found that a single dose of ELQ-400 rapidly induced stasis in blood-stage parasites, which was associated with a rapid reduction in parasitemia in vivo. ELQ-400 also exhibited a low propensity for drug resistance and was active against atovaquone-resistant P. falciparum strains with point mutations in cyt bc1. Ultimately, ELQ-400 shows that cyt bc1 inhibitors can function as single-dose, blood-stage antimalarials and is the first compound to provide combined treatment, prophylaxis, and transmission blocking activity for malaria after a single oral administration. This remarkable multi-stage efficacy suggests that metabolic therapies, including cyt bc1 inhibitors, may be valuable additions to the collection of single-dose antimalarials in current development.

Author Notes

* Address correspondence to Aaron Nilsen, Oregon Health and Science University, 3181 SW Sam Jackson Park Rd., Portland, OR 97239, E-mail: nilsena@ohsu.edu, or Michael K. Riscoe, VA Medical Center, 3710 SW US Veterans Hospital Rd., Portland, OR 97239, E-mail: riscoem@ohsu.edu

Financial support: This work was supported by US DOD PRMRP grant PR130649 and NIH NIAID grants AI100569, AI079182, and AI028398. Additional support was provided by the United States Department of Veterans Affairs and the Stanley Medical Research Institute. The IVIS Spectrum was purchased with support from NIH Shared Instrumentation Grant S10RR027308 awarded to the Albert Einstein College of Medicine.

Disclosure: Some of the authors are listed as co-authors on US patent 2014/00458888 related to this work. This statement is made in the interest of full disclosure and not because the authors consider this to be a conflict of interest.

Authors' addresses: Allison M. Stickles, Erin Meermeier, David J. Hinrichs, and Michael K. Riscoe, Departments of Physiology and Pharmacology, Microbiology and Molecular Immunology, Oregon Health and Science University, Portland, OR, E-mails: stickles@ohsu.edu, riscoe@ohsu.edu, hinrichs@ohsu.edu, riscoem@ohsu.edu, and riscoem@ohsu.edu. Li-Min Ting and Kami Kim, Departments of Medicine, Pathology, and Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY, E-mails: li-min.ting@einstein.yu.edu and kami.kim@einstein.yu.edu. Joanne M. Morrisey, Michael W. Mather, April M. Pershing, and Akhil B. Vaidya, Department of Microbiology and Immunology, Drexel University College of Medicine, Philadelphia, PA, E-mails: joanne.morrisey@drexelmed.edu, michael.mather@drexelmed.edu, amp352@drexel.edu, and akhil.vaidya@drexelmed.edu. Yuexin Li, Isaac P. Forquer, Galen P. Miley, Sovitj Pou, Rolf W. Winter, Jane X. Kelly, and Aaron Nilsen, VA Medical Center, Portland, OR, E-mails: liyu@ohsu.edu, forqueri@ohsu.edu, galen.p.miley@gmail.com, sovitjpou@gmail.com, winterr@ohsu.edu, kellyja@ohsu.edu, and nilsena@ohsu.edu.

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