Inhibitors of nonhousekeeping functions of the apicoplast defy delayed death in Plasmodium falciparum.
Targeting of apicoplast replication and protein synthesis in the apicomplexan Toxoplasma gondii has conventionally been associated with the typical "delayed death" phenotype, characterized by the death of parasites only in the generation following drug intervention. We demonstrate that antibiotics like clindamycin, chloramphenicol, and tetracycline, inhibitors of prokaryotic protein synthesis, invoke the delayed death phenotype in Plasmodium falciparum, too, as evident from a specific reduction of apicoplast genome copy number. Interestingly, however, molecules like triclosan, cerulenin, fops, and NAS-91, inhibitors of the recently discovered fatty acid synthesis pathway, and succinyl acetone, an inhibitor of heme biosynthesis that operates in the apicoplast of the parasite, display rapid and striking parasiticidal effects. Our results draw a clear distinction between apicoplast functions per se and the apicoplast as the site of metabolic pathways, which are required for parasite survival, and thus subserve the development of novel antimalarial therapy.
Ramya
T N C
TN
Molecular Biophysics Unit, Indian Institute of Science, Bangalore 560012, India.
Mishra
Satyendra
S
Karmodiya
Krishanpal
K
Surolia
Namita
N
Surolia
Avadhesha
A
D000096:Acetone / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D000962:Antimalarials / Q000145:classification / Q000494:pharmacology*; D017963:Azithromycin / Q000494:pharmacology; D002569:Cerulenin / Q000494:pharmacology; D002701:Chloramphenicol / Q000494:pharmacology; D002981:Clindamycin / Q000494:pharmacology; D004912:Erythrocytes / Q000469:parasitology; D005227:Fatty Acids / Q000096:biosynthesis; D018628:Gene Dosage; D006801:Humans; D015388:Organelles / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D021261:Parasitic Sensitivity Tests; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D015800:Protozoan Proteins / Q000378:metabolism; D013752:Tetracycline / Q000494:pharmacology; D008063:Thioctic Acid / Q000494:pharmacology; D014260:Triclosan / Q000494:pharmacology
D000962:Antimalarials; D005227:Fatty Acids; D015800:Protozoan Proteins; D000096:Acetone; D002569:Cerulenin; D002981:Clindamycin; D014260:Triclosan; D002701:Chloramphenicol; D008063:Thioctic Acid; D017963:Azithromycin; D013752:Tetracycline