Cellular and molecular actions of dinitroaniline and phosphorothioamidate herbicides on Plasmodium falciparum: Tubulin as a specific antimalarial target

Fennell, Brian J.; Naughton, Julie; Dempsey, Enda; Bell, Angus

doi:10.1016/j.molbiopara.2005.08.020

Cited by 87 publications

(86 citation statements)

References 50 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…In some studies using fluorescent reagents against tubulins, relatively long (2 to 4 m) and sometimes astral microtubules have been described inside nuclei in blood-stage P. falciparum (24,25,53), and it has been postulated that these structures are hemispindles similar to those described by TEM studies of mitosis (Fig. 2).…”

Section: Figmentioning

confidence: 85%

“…Studies using fluorescent probes against tubulins have highlighted the variety of P. falciparum microtubule structures (53) that are comprised of differentially expressed tubulin isotypes and posttranslational modifications (24,38,53). In addition, tubulin fluorescence has been used to correlate spindle development with the nuclear cycle (7,42,53) and to characterize the disruption of mitotic structures in response to antimalarial drug treatments (25,74). These studies have indicated that during the later stages of schizogony when the parasite becomes crowded with nuclei, the maximum lengths of the mitotic spindles appear to become progressively smaller in the limited space (42,53).…”

Section: Figmentioning

confidence: 99%

“…4, row iii, f). In another example of apparent scale inconsistency, fluorescence studies have also identified short, discrete plaques in P. falciparum nuclei that stain intensely with anti-microtubule reagents (7,24,25,53), and these structures have been interpreted as the MTOCs that are visible by TEM. These tubulin-rich plaques have been reported in the literature with a variety of sizes.…”

Section: Figmentioning

confidence: 99%

See 2 more Smart Citations

Mitosis in the Human Malaria Parasite Plasmodium falciparum

2011

View full text Add to dashboard Cite

Malaria is caused by intraerythrocytic protozoan parasites belonging to Plasmodium spp. (phylum Apicomplexa) that produce significant morbidity and mortality, mostly in developing countries. Plasmodium parasites have a complex life cycle that includes multiple stages in anopheline mosquito vectors and vertebrate hosts. During the life cycle, the parasites undergo several cycles of extreme population growth within a brief span, and this is critical for their continued transmission and a contributing factor for their pathogenesis in the host. As with other eukaryotes, successful mitosis is an essential requirement for Plasmodium reproduction; however, some aspects of Plasmodium mitosis are quite distinct and not fully understood. In this review, we will discuss the current understanding of the architecture and key events of mitosis in Plasmodium falciparum and related parasites and compare them with the traditional mitotic events described for other eukaryotes. SERIAL MITOSIS IS A COMMON THEME IN MALARIA PARASITE REPRODUCTIONThere are four critical points in the life cycle of Plasmodium parasites in which a small number of parasites rapidly multiply to generate much larger populations (60). These life cycle stages are male gamete development (72), sporozoite formation (5, 13), liver-stage development (68), and blood-stage asexual reproduction (9, 60). The first two of these processes occur within the mosquito vector, and the second two processes take place in the vertebrate host. During each of these Plasmodium life cycle stages, the parasites increase their numbers by using serial rounds of mitosis to create multinuclear cells and then orchestrating mass cytokinesis events to release their progeny (71). Mitosis is the process by which eukaryotic cells segregate their chromosomes in preparation for cell division (33,47,51).To create male gametes in preparation for sexual reproduction, the parasite begins with a haploid (1n) cell called a microgametocyte which is ingested by the mosquito during a blood meal (34,72). Within 12 min, this microgametocyte undergoes three rapid rounds of DNA synthesis and mitosis to generate a cell with an 8n genomic complement (35,36,73). Over the next 3 min, these genomes separate from one another and eight new haploid (1n) male gametes begin to assemble from the surface of the original cell (4, 69, 71).Within the mosquito midgut, a small number of the male gametes will fuse with female gametes that have also developed in this compartment, and this fusion will create diploid (2n) zygotes (15). These zygotes develop into motile ookinetes (4n) (36) that ultimately become embedded in the basal lamina beneath the midgut epithelial wall as oocysts (14). Over the course of several days, a single oocyst undergoes 10 to 11 rounds of DNA synthesis and mitosis to create a syncytial cell (sporoblast) with thousands of nuclei (61,70,82). In a massive cytokinesis event, thousands of haploid (1n) daughter sporozoites assemble from the surface of the mother cell (61, 67), and these infective sporozo...

show abstract

Section: Figmentioning

confidence: 85%

Section: Figmentioning

confidence: 99%

Section: Figmentioning

confidence: 99%

See 1 more Smart Citation

Mitosis in the Human Malaria Parasite Plasmodium falciparum

2011

View full text Add to dashboard Cite

show abstract

“…52) P. falciparum is much more sensitive to trifluralin than are humans. 53) Toxoplasma gondii is highly sensitive to trifluralin and other dinitroaniline mitotic inhibitors. 54) Although 15 out of 26 herbicides and phytotoxins tested have their target site in the chloroplast, they had only negligible or moderate action against the malaria parasite in vitro.…”

Section: Discussionmentioning

confidence: 99%

A Survey of Synthetic and Natural Phytotoxic Compounds and Phytoalexins as Potential Antimalarial Compounds

Bajsa

Singh

Nanayakkara

et al. 2007

Biological & Pharmaceutical Bulletin

View full text Add to dashboard Cite

The apicomplexan parasites pathogens such as Plasmodium spp. possess an apicoplast, a plastid organelle similar to those of plants. The apicoplast has some essential plant-like metabolic pathways and processes, making these parasites susceptible to inhibitors of these functions. The main objective of this paper is to determine if phytotoxins with plastid target sites are more likely to be good antiplasmodial compounds than are those with other modes of action. The antiplasmodial activities of some compounds with established phytotoxic action were determined in vitro on a chloroquine (CQ) sensitive (D6, Sierra Leone) strain of Plasmodium falciparum. In this study, we provide in vitro activities of almost 50 such compounds, as well as a few phytoalexins against P. falciparum. Endothall, anisomycin, and cerulenin had sufficient antiplasmodial action to be considered as new lead antimalarial structures. Some derivatives of fusicoccin possessed markedly improved antiplasmodial action than the parent compound. Our results suggest that phytotoxins with plastid targets may not necessarily be better antiplasmodials than those that act at other molecular sites. The herbicides, phytotoxins and the phytoalexins reported here with significant antiplasmodial activity may be useful probes for identification of new antimalarial drug targets and may also be used as new lead structures for new antiplasmodial drug discovery.

show abstract

“…Initially, these oryzalin analogs were evaluated in vitro for their ability to inhibit the polymerization of tubulin purified from L. amazonensis (Werbovetz et al, 1999), and ongoing drug discovery efforts against this promising target will continue to require in vitro evaluation of novel compounds against purified leishmanial tubulin. Reports detailing the expression of tubulin from parasites have appeared (MacDonald et al, 2003;Fennell et al, 2006), some of which have demonstrated the assembly of recombinant αβ tubulin (Oxberry et al, 2001;MacDonald et al, 2004). No such expression system currently exists for the leishmanial protein, however, and antileishmanial drug discovery work will continue to rely on the purification of tubulin directly from the parasite in the near future.…”

Section: Introductionmentioning

confidence: 99%

Leishmania tarentolae: Purification and characterization of tubulin and its suitability for antileishmanial drug screening

Yakovich

Ragone

Alfonzo

et al. 2006

Experimental Parasitology

View full text Add to dashboard Cite

Previously, tubulin has been purified from Leishmania amazonensis and used to identify novel molecules with selective antimitotic activity. However, Leishmania amazonensis is pathogenic and requires a relatively expensive medium for large-scale cultivation. Herein, the purification and characterization of tubulin from the non-pathogenic Leishmania tarentolae is reported, together with the sequence of α-and β-tubulin from this organism. This protein was purified by sonication, diethylaminoethyl-Sepharose chromatography, and one assembly-disassembly cycle in 1% overall recovery based on total cellular protein. L. tarentolae tubulin was indistinguishable from the corresponding L. amazonensis protein in terms of binding affinity for dinitroaniline sulfanilamides and sensitivity to assembly inhibition by these compounds. The amino acid sequences derived from the L. tarentolae α-and β-tubulin genes were 99.6% and 99.4% identical to the corresponding amino acid sequences from the L. major Friedlin strain. These results indicate that tubulin from L. tarentolae is suitable for use in drug screening.

show abstract

Cellular and molecular actions of dinitroaniline and phosphorothioamidate herbicides on Plasmodium falciparum: Tubulin as a specific antimalarial target

Cited by 87 publications

References 50 publications

Mitosis in the Human Malaria Parasite Plasmodium falciparum

Mitosis in the Human Malaria Parasite Plasmodium falciparum

A Survey of Synthetic and Natural Phytotoxic Compounds and Phytoalexins as Potential Antimalarial Compounds

Leishmania tarentolae: Purification and characterization of tubulin and its suitability for antileishmanial drug screening

Contact Info

Product

Resources

About