Inhibition of cytochrome bc1 as a strategy for single-dose, multi-stage antimalarial therapy.
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.
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.
Allison M
AM
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.
Li-Min
LM
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.
Joanne M
JM
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.
Yuexin
Y
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.
Michael W
MW
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.
Erin
E
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.
April M
AM
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.
Isaac P
IP
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.
Galen P
GP
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.
Sovitj
S
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.
Rolf W
RW
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.
David J
DJ
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.
Jane X
JX
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.
Kami
K
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.
Akhil B
AB
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 nilsena@ohsu.edu riscoem@ohsu.edu.
Michael K
MK
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 nilsena@ohsu.edu riscoem@ohsu.edu.
Aaron
A
Nilsen
D000818:Animals; D000962:Antimalarials / Q000008:administration & dosage / Q000627:therapeutic use*; D004351:Drug Resistance; D014450:Electron Transport Complex III / Q000037:antagonists & inhibitors* / Q000378:metabolism; D005260:Female; D016778:Malaria, Falciparum / Q000188:drug therapy*; D051379:Mice; D018512:Parasitemia / Q000188:drug therapy; D010647:Phenyl Ethers / Q000627:therapeutic use*; D010963:Plasmodium falciparum / Q000187:drug effects; D010967:Plasmodium yoelii / Q000187:drug effects; D015363:Quinolones / Q000627:therapeutic use*
D000962:Antimalarials; C000600454:ELQ-400; D010647:Phenyl Ethers; D015363:Quinolones; D014450:Electron Transport Complex III