Publication: Properties of plasmodium falciparum with a deleted apicoplast DNA gyrase
Issued Date
2021-09-01
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ISSN
10986596
00664804
00664804
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2-s2.0-85112822873
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Mahidol University
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SCOPUS
Bibliographic Citation
Antimicrobial Agents and Chemotherapy. Vol.65, No.9 (2021)
Suggested Citation
Soo Nee Tan, Devaraja G. Mudeppa, Sreekanth Kokkonda, John White, Rapatbhorn Patrapuvich, Pradipsinh K. Rathod Properties of plasmodium falciparum with a deleted apicoplast DNA gyrase. Antimicrobial Agents and Chemotherapy. Vol.65, No.9 (2021). doi:10.1128/AAC.00586-21 Retrieved from: https://repository.li.mahidol.ac.th/handle/20.500.14594/77904
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Title
Properties of plasmodium falciparum with a deleted apicoplast DNA gyrase
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Abstract
Malaria parasites have three genomes: a nuclear genome, a mitochondrial genome, and an apicoplast genome. Since the apicoplast is a plastid organelle of prokaryotic origin and has no counterpart in the human host, it can be a source of novel targets for antimalarials. Plasmodium falciparum DNA gyrase (PfGyr) A and B subunits both have apicoplast- targeting signals. First, to test the predicted localization of this enzyme in the apicoplast and the breadth of its function at the subcellular level, nuclear-encoded PfGyrA was disrupted using CRISPR/Cas9 gene editing. Isopentenyl pyrophosphate (IPP) is known to rescue parasites from apicoplast inhibitors. Indeed, successful growth and characterization of PfDGyrA was possible in the presence of IPP. PfGyrA disruption was accompanied by loss of plastid acyl-carrier protein (ACP) immunofluorescence and the plastid genome. Second, ciprofloxacin, an antibacterial gyrase inhibitor, has been used for malaria prophylaxis, but there is a need for a more detailed description of the mode of action of ciprofloxacin in malaria parasites. As predicted, PfDGyrA clone supplemented with IPP was less sensitive to ciprofloxacin but not to the nuclear topoisomerase inhibitor etoposide. At high concentrations, however, ciprofloxacin continued to inhibit IPP-rescued PfDGyrA, possibly suggesting that ciprofloxacin may have an additional nonapicoplast target in P. falciparum. Overall, we confirm that PfGyrA is an apicoplast enzyme in the malaria parasite, essential for bloodstage parasites, and a possible target of ciprofloxacin but perhaps not the only target.