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bioRxiv · 10.1101/2020.06.11.146407

Doxycycline has Distinct Apicoplast-Specific Mechanisms of Antimalarial Activity

Guo, P.·Nalder, S.-a.·Okada, M.·Sigala, P. A.
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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 M serum concentrations. DOX concentrations >5 M kill parasites with first-cycle activity but have been ascribed to off-target mechanisms outside the apicoplast. We report that 10 M 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 M 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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Guo, P., Nalder, S.-a., Okada, M., Sigala, P. A.. 2020-06-11. Doxycycline has Distinct Apicoplast-Specific Mechanisms of Antimalarial Activity. https://doi.org/10.1101/2020.06.11.146407

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