About: Doxycycline has Distinct Apicoplast-Specific Mechanisms of Antimalarial Activity

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An Entity of Type : schema:ScholarlyArticle, within Data Space : wasabi.inria.fr associated with source document(s)

Attributes	Values
type	Academic Article research paper schema:ScholarlyArticle
isDefinedBy	Covid-on-the-Web dataset
has title	Doxycycline has Distinct Apicoplast-Specific Mechanisms of Antimalarial Activity
Creator	Guo, Ping Nalder, Shai-Anne Okada, Megan Sigala, Paul
Source	BioRxiv
abstract	Doxycycline (DOX) is a key antimalarial drug that is thought to kill Plasmodium falciparum parasites by blocking protein translation in the essential apicoplast organelle. Although parasite resistance to DOX has not emerged, clinical use is primarily limited to prophylaxis due to delayed second-cycle parasite death at 1-3 μM, the DOX concentration readily achieved in human plasma at current dosing. Slow antiparasitic activity is thought to be a fundamental limitation of DOX and other antibiotics that target apicoplast maintenance. We report that slightly higher 8-10 μM DOX concentrations kill parasites with first-cycle activity that blocks apicoplast biogenesis. This faster activity is rescued by exogenous isopentenyl pyrophosphate, an essential apicoplast product, confirming an apicoplast-specific target. Exogenous iron rescues first- but not second-cycle activity by 1 or 10 μM DOX, revealing that first-cycle activity involves a metal-dependent mechanism that is distinct from the canonical delayed-death mechanism. These results provide a new paradigm for understanding fundamental antiparasitic mechanisms of DOX and suggest the possibility of repurposing DOX as a faster-acting antimalarial at higher dosing, which remains well tolerated. Multiple mechanisms of DOX activity would be expected to limit parasite resistance.
has issue date	2020-06-11(xsd:dateTime)
bibo:doi	10.1101/2020.06.11.146407
has license	biorxiv
sha1sum (hex)	c9ddcb716d8f48b08af8942141897d535590b373
schema:url	https://doi.org/10.1101/2020.06.11.146407
resource representing a document's title	Doxycycline has Distinct Apicoplast-Specific Mechanisms of Antimalarial Activity
schema:publication	bioRxiv
resource representing a document's body	covid:c9ddcb716d8f48b08af8942141897d535590b373#body_text
is schema:about of	named entity 'Doxycycline' named entity 'Antimalarial' named entity 'Apicoplast' named entity 'Antimalarial' named entity 'Doxycycline' named entity 'intraerythrocytic' named entity 'apicoplast' named entity 'parasites' named entity 'exogenous' named entity 'competitive displacement' named entity 'iron' named entity 'doxycycline' named entity 'FeCl3' named entity 'apicoplast' named entity 'apicoplast' named entity 'intraerythrocytic' named entity 'apicoplast' named entity 'ribosomes' named entity 'apicoplast' named entity 'Pharmacokinetic' named entity 'Doxycycline' named entity 'intraerythrocytic' named entity 'Tetracyclines' named entity 'malaria prevention' named entity 'P. falciparum' named entity 'antibiotics' named entity 'apicoplast' named entity 'GFP' named entity 'parasite' named entity 'ribosomal translation' named entity 'apicoplast' named entity 'RPMI' named entity 'exogenous' named entity 'prophylaxis' named entity 'toxicity' named entity 'labile' named entity 'hydroxyl' named entity 'apicoplast' named entity 'apicoplast' named entity 'parasite' named entity 'drug resistance' named entity 'tetracycline' named entity 'ribosomal' named entity 'iron' named entity 'bioavailability' named entity 'iron' named entity 'trivalent' named entity 'tetracycline repressor' named entity 'malaria prevention' named entity 'apicoplast' named entity 'parasite resistance' named entity 'association constant' named entity 'human plasma' named entity 'iron' named entity 'Parasites' named entity 'growth cycle' named entity '3, 4' named entity 'P. falciparum' named entity 'diketo' named entity 'organelle' named entity 'apicoplast' named entity 'long-lasting' named entity 'isoprenoid biosynthesis' named entity 'apicoplast' named entity 'IPP' named entity 'IPP' named entity 'CaCl2' named entity 'parasite resistance' named entity 'protein translation' named entity 'organelle' named entity 'parasites' named entity 'apicoplast' named entity 'cellular uptake' named entity 'parasites' named entity 'isopentenyl pyrophosphate' named entity 'antiparasitic' named entity 'antiparasitic' named entity 'apicoplast' named entity 'Africa' named entity 'vaccine' named entity 'P. falciparum'

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