Multiple antibiotics exert delayed effects against the Plasmodium falciparum apicoplast.
Several classes of antibiotics exert antimalarial activity. The mechanisms of action of antibiotics against malaria parasites have been unclear, and prior studies have led to conflicting results, in part because they studied antibiotics at suprapharmacological concentrations. We examined the antimalarial effects of azithromycin, ciprofloxacin, clindamycin, doxycycline, and rifampin against chloroquine-resistant (W2) and chloroquine-sensitive (3D7) Plasmodium falciparum strains. At clinically relevant concentrations, rifampin killed parasites quickly, preventing them from initiating cell division. In contrast, pharmacological concentrations of azithromycin, ciprofloxacin, clindamycin, and doxycycline were relatively inactive against parasites initially but exerted a delayed death effect, in which the progeny of treated parasites failed to complete erythrocytic development. The drugs that caused delayed death did not alter the distribution of apicoplasts into developing progeny. However, the apicoplasts inherited by the progeny of treated parasites were abnormal. The loss of apicoplast function became apparent as the progeny of antibiotic-treated parasites initiated cell division, with the failure of schizonts to fully mature or for erythrocyte rupture to take place. These findings explain the slow antimalarial action of multiple antibiotics.
Dahl
Erica L
EL
Department of Medicine, University of California San Francisco, San Francisco, CA 94143-0811, USA.
Rosenthal
Philip J
PJ
D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D000962:Antimalarials / Q000494:pharmacology*; D004351:Drug Resistance; D005434:Flow Cytometry; D049452:Green Fluorescent Proteins / Q000378:metabolism; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000235:genetics / Q000254:growth & development; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D059005:Topoisomerase II Inhibitors
D000900:Anti-Bacterial Agents; D000962:Antimalarials; D011500:Protein Synthesis Inhibitors; D059005:Topoisomerase II Inhibitors; D049452:Green Fluorescent Proteins
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