Chloramphenicol in Malaria

F, Ruizsanchez; M, Quezada; Paredes, M.; Casillas, Josefina; Riebeling, R

doi:10.4269/ajtmh.1952.1.936

Cited by 11 publications

(5 citation statements)

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“…This is not surprising, as two bacterial protein synthesis inhibitors, azithromycin and doxycycline, have confirmed apicoplast targets and delayed death (33). Inhibiting apicoplast genome replication with drugs specifically targeting prokaryotic DNA gyrase activity, such as the fluoroquinolone ciprofloxacin (103,104), or protein translation with any of four classes of antibacterials (chloramphenicol, tetracyclines, lincosamides, and macrolides) (12,18,33,55,94,(105)(106)(107) or a tRNA synthesis inhibitor (mupirocin) all cause characteristic delayed death and were confirmed to primarily target the apicoplast in our assays (Table 2 and Fig. 2 and 5) (37).…”

Section: Discussionmentioning

confidence: 99%

“…Huge investments are required to find new drugs and identify their targets, so a better understanding of the mode of action of existing antimalarials is an effective use of resources. The use of antibacterial drugs against malaria started long before the apicoplast was identified in the malaria parasite (88)(89)(90)(91)(92)(93)(94)(95). Nowadays, we appreciate that the bacterialike housekeeping machinery of the apicoplast, such as DNA replication, transcription, translation, and posttranslational modification, as well as metabolic pathways for synthesis of fatty acids, isoprenoid precursors, heme, and iron-sulfur complexes in the organelle make it an attractive drug target (17-30, 51, 96-102).…”

Section: Discussionmentioning

confidence: 99%

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Validation of Putative Apicoplast-Targeting Drugs Using a Chemical Supplementation Assay in Cultured Human Malaria Parasites

Uddin

McFadden

Goodman

2018

Antimicrob Agents Chemother

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Malaria parasites contain a relict plastid, the apicoplast, which is considered an excellent drug target due to its bacterial-like ancestry. Numerous parasiticidals have been proposed to target the apicoplast, but few have had their actual targets substantiated. Isopentenyl pyrophosphate (IPP) production is the sole required function of the apicoplast in the blood stage of the parasite life cycle, and IPP supplementation rescues parasites from apicoplast-perturbing drugs. Hence, any drug that kills parasites when IPP is supplied in culture must have a nonapicoplast target. Here, we use IPP supplementation to discriminate whether 23 purported apicoplast-targeting drugs are on- or off-target. We demonstrate that a prokaryotic DNA replication inhibitor (ciprofloxacin), several prokaryotic translation inhibitors (chloramphenicol, doxycycline, tetracycline, clindamycin, azithromycin, erythromycin, and clarithromycin), a tRNA synthase inhibitor (mupirocin), and two IPP synthesis pathway inhibitors (fosmidomycin and FR900098) have apicoplast targets. Intriguingly, fosmidomycin and FR900098 leave the apicoplast intact, whereas the others eventually result in apicoplast loss. Actinonin, an inhibitor of bacterial posttranslational modification, does not produce a typical delayed-death response but is rescued with IPP, thereby confirming its apicoplast target. Parasites treated with putative apicoplast fatty acid pathway inhibitors could not be rescued, demonstrating that these drugs have their primary targets outside the apicoplast, which agrees with the dispensability of the apicoplast fatty acid synthesis pathways in the blood stage of malaria parasites. IPP supplementation provides a simple test of whether a compound has a target in the apicoplast and can be used to screen novel compounds for mode of action.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Validation of Putative Apicoplast-Targeting Drugs Using a Chemical Supplementation Assay in Cultured Human Malaria Parasites

Uddin

McFadden

Goodman

2018

Antimicrob Agents Chemother

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“…Rifampin (2), chloramphenicol (12,39), and erythromycin (53) have demonstrable antimalarial effects in animal models, whereas tetracyclines (11,13,32,36,54) and clindamycin (7,10,26,37) have been shown to be effective against P. falciparum in humans. Although no data are available on the mechanism(s) of antimalarial action of these drugs, it has been suggested that they act on parasite mitochondria, which, like all eucaryotic mitochondria, probably contain 70S ribosomes (16; J. J. Blum, A. Yayon, F. Friedman, and H. Ginsburg, J.…”

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confidence: 99%

Oxygen- and time-dependent effects of antibiotics and selected mitochondrial inhibitors on Plasmodium falciparum in culture

Divo¹,

Geary²,

Jensen³

1985

Antimicrob Agents Chemother

123

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Several antibiotics which inhibit protein synthesis on 70S ribosomes, including clindamycin, pirlimycin, 4'-pentyl-N-demethyl clindamycin, four tetracyclines, chloramphenicol, thiamphenicol, and erythromycin, had antimalarial effects against Plasmodium falciparum in culture which were greatly influenced by the duration of drug exposure and by oxygen tension. In 96-h incubations, potency was increased by a factor of up to 106 over the first 48-h period and by a factor of up to 104 in 15% 02 versus 1% 02. Two aminoglycosides, kanamycin and tobramycin, had no antimalarial activity. Rifampin and nalidixic acid, which inhibit nucleic acid synthesis, were not similar to the 70S inhibitors. The mitochondrial inhibitors Janus Green, rhodamine 123, antimycin Al, and 8-methylamino-8-desmethyl riboflavin had activities which were influenced by the duration of exposure and oxygen tension. Quinoline-containing antimalarial agents, ionophores, and other antimalarial drugs were influenced to a minor extent by the duration of exposure but were not affected by oxygen tension. These data can best be explained by the hypothesis that antimalarial 70S ribosome-specific protein synthesis inhibitors are toxic to the parasites by acting on the mitochondrion.

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“…Nevertheless, Ruiz-Sanchez et al (1951) claimed good results clinically, but found cure was slower than with routine antimalarial drugs. In our case, over the four days aureomycin was given, fever and dyspnoea slowly subsided, and just before mepacrine was substituted scanty falciparum parasites were found in the thick-drop film, confirming the definite but poor therapeutic action of aureomycin.…”

Section: Treatmentmentioning

confidence: 99%

Congenital Malaria in England

Dimson¹

1954

BMJ

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Chloramphenicol in Malaria

Cited by 11 publications

References 0 publications

Validation of Putative Apicoplast-Targeting Drugs Using a Chemical Supplementation Assay in Cultured Human Malaria Parasites

Validation of Putative Apicoplast-Targeting Drugs Using a Chemical Supplementation Assay in Cultured Human Malaria Parasites

Oxygen- and time-dependent effects of antibiotics and selected mitochondrial inhibitors on Plasmodium falciparum in culture

Congenital Malaria in England

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