Doxycycline has distinct apicoplast-specific mechanisms of antimalarial activity
- University of Utah School of Medicine, United States
Abstract
Doxycycline (DOX) is a key antimalarial drug thought to kill Plasmodium parasites by blocking protein translation in the essential apicoplast organelle. Clinical use is primarily limited to prophylaxis due to delayed second-cycle parasite death at 1-3 µM serum concentrations. DOX concentrations >5 µM kill parasites with first-cycle activity but have been ascribed to off-target mechanisms outside the apicoplast. We report that 10 µM DOX blocks apicoplast biogenesis in the first cycle and is rescued by isopentenyl pyrophosphate, an essential apicoplast product, confirming an apicoplast-specific mechanism. Exogenous iron rescues parasites and apicoplast biogenesis from first- but not second-cycle effects of 10 µM DOX, revealing that first-cycle activity involves a metal-dependent mechanism distinct from the delayed-death mechanism. These results critically expand the paradigm for understanding the fundamental antiparasitic mechanisms of DOX and suggest repurposing DOX as a faster-acting antimalarial at higher dosing whose multiple mechanisms would be expected to limit parasite resistance.
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All data reported or described in this manuscript are available and included in the main and supplemental figures and in the microscopy source data file.
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Funding
National Institute of Diabetes and Digestive and Kidney Diseases (T32DK007115)
- Megan Okada
National Heart and Lung Institute (R25HL108828)
- Shai-anne Nalder
National Institute of Diabetes and Digestive and Kidney Diseases (U54DK110858)
- Paul A Sigala
Burroughs Wellcome Fund (1011969)
- Paul A Sigala
Pew Charitable Trusts (32099)
- Paul A Sigala
National Institute of General Medical Sciences (R35GM133764)
- Paul A Sigala
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Copyright
© 2020, Okada et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Doxycycline has distinct apicoplast-specific mechanisms of antimalarial activity
eLife 9:e60246.
https://doi.org/10.7554/eLife.60246
