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The Spiroindolone KAE609 Does Not Induce Dormant Ring Stages in Plasmodium falciparum Parasites
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| Zeitschriftentitel: | Antimicrobial Agents and Chemotherapy |
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| Personen und Körperschaften: | , , , , |
| In: | Antimicrobial Agents and Chemotherapy, 60, 2016, 9, S. 5167-5174 |
| Format: | E-Article |
| Sprache: | Englisch |
| veröffentlicht: |
American Society for Microbiology
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| Schlagwörter: |
| Zusammenfassung: | <jats:title>ABSTRACT</jats:title> <jats:p> <jats:italic>In vitro</jats:italic> drug treatment with artemisinin derivatives, such as dihydroartemisinin (DHA), results in a temporary growth arrest (i.e., dormancy) at an early ring stage in <jats:named-content xmlns:xlink="http://www.w3.org/1999/xlink" content-type="genus-species" xlink:type="simple">Plasmodium falciparum</jats:named-content> . This response has been proposed to play a role in the recrudescence of <jats:named-content xmlns:xlink="http://www.w3.org/1999/xlink" content-type="genus-species" xlink:type="simple">P. falciparum</jats:named-content> infections following monotherapy with artesunate and may contribute to the development of artemisinin resistance in <jats:named-content xmlns:xlink="http://www.w3.org/1999/xlink" content-type="genus-species" xlink:type="simple">P. falciparum</jats:named-content> malaria. We demonstrate here that artemether does induce dormant rings, a finding which further supports the class effect of artemisinin derivatives in inducing the temporary growth arrest of <jats:named-content xmlns:xlink="http://www.w3.org/1999/xlink" content-type="genus-species" xlink:type="simple">P. falciparum</jats:named-content> parasites. In contrast and similarly to lumefantrine, the novel and fast-acting spiroindolone compound KAE609 does not induce growth arrest at the early ring stage of <jats:named-content xmlns:xlink="http://www.w3.org/1999/xlink" content-type="genus-species" xlink:type="simple">P. falciparum</jats:named-content> and prevents the recrudescence of DHA-arrested rings at a low concentration (50 nM). Our findings, together with previous clinical data showing that KAE609 is active against artemisinin-resistant K13 mutant parasites, suggest that KAE609 could be an effective partner drug with a broad range of antimalarials, including artemisinin derivatives, in the treatment of multidrug-resistant <jats:named-content xmlns:xlink="http://www.w3.org/1999/xlink" content-type="genus-species" xlink:type="simple">P. falciparum</jats:named-content> malaria. </jats:p> |
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| Umfang: | 5167-5174 |
| ISSN: |
0066-4804
1098-6596 |
| DOI: | 10.1128/aac.02838-15 |