Targeting malaria parasite invasion of red blood cells as an antimalarial strategy

Burns, Amy L.; Dans, Madeline G; Balbin, Juan Miguel; Koning-Ward, Tania F de; Gilson, Paul R.; Beeson, James G.; Boyle, Michelle J.; Wilson, Danny W.

doi:10.1093/femsre/fuz005

Cited by 74 publications

(53 citation statements)

References 202 publications

(240 reference statements)

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“…Importantly, assays where merozoites were treated directly prior to compound removal and addition of RBCs to begin invasion show that the invasion inhibitory activity of azithromycin and analogues is directed against the merozoite and not against the RBC. A number of invasion inhibitory antimalarial strategies are being pursued globally (reviewed in [62]), and there remains the possibility that further improvements in azithromycin analogue invasion inhibitory IC 50 are achievable with additional development.…”

Section: Discussionmentioning

confidence: 99%

Retargeting azithromycin analogues to have dual-modality antimalarial activity

et al. 2020

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Background Resistance to front-line antimalarials (artemisinin combination therapies) is spreading, and development of new drug treatment strategies to rapidly kill Plasmodium spp. malaria parasites is urgently needed. Azithromycin is a clinically used macrolide antibiotic proposed as a partner drug for combination therapy in malaria, which has also been tested as monotherapy. However, its slow-killing ‘delayed-death’ activity against the parasite’s apicoplast organelle and suboptimal activity as monotherapy limit its application as a potential malaria treatment. Here, we explore a panel of azithromycin analogues and demonstrate that chemical modifications can be used to greatly improve the speed and potency of antimalarial action. Results Investigation of 84 azithromycin analogues revealed nanomolar quick-killing potency directed against the very earliest stage of parasite development within red blood cells. Indeed, the best analogue exhibited 1600-fold higher potency than azithromycin with less than 48 hrs treatment in vitro. Analogues were effective against zoonotic Plasmodium knowlesi malaria parasites and against both multi-drug and artemisinin-resistant Plasmodium falciparum lines. Metabolomic profiles of azithromycin analogue-treated parasites suggested activity in the parasite food vacuole and mitochondria were disrupted. Moreover, unlike the food vacuole-targeting drug chloroquine, azithromycin and analogues were active across blood-stage development, including merozoite invasion, suggesting that these macrolides have a multi-factorial mechanism of quick-killing activity. The positioning of functional groups added to azithromycin and its quick-killing analogues altered their activity against bacterial-like ribosomes but had minimal change on ‘quick-killing’ activity. Apicoplast minus parasites remained susceptible to both azithromycin and its analogues, further demonstrating that quick-killing is independent of apicoplast-targeting, delayed-death activity. Conclusion We show that azithromycin and analogues can rapidly kill malaria parasite asexual blood stages via a fast action mechanism. Development of azithromycin and analogues as antimalarials offers the possibility of targeting parasites through both a quick-killing and delayed-death mechanism of action in a single, multifactorial chemotype.

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Section: Discussionmentioning

confidence: 99%

Retargeting azithromycin analogues to have dual-modality antimalarial activity

et al. 2020

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“…The merozoite invasion organelles harbour essential antigens that are the targets of therapeutic interventions aimed at preventing blood-stage parasite replication [3][4][5][6] . The contents of micronemes are released first and are responsible for coordinating initial attachment events 7 .…”

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confidence: 99%

PfCERLI1 is a conserved rhoptry associated protein essential for Plasmodium falciparum merozoite invasion of erythrocytes

et al. 2020

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The disease-causing blood-stage of the Plasmodium falciparum lifecycle begins with invasion of human erythrocytes by merozoites. Many vaccine candidates with key roles in binding to the erythrocyte surface and entry are secreted from the large bulb-like rhoptry organelles at the apical tip of the merozoite. Here we identify an essential role for the conserved protein P. falciparum Cytosolically Exposed Rhoptry Leaflet Interacting protein 1 (PfCERLI1) in rhoptry function. We show that PfCERLI1 localises to the cytosolic face of the rhoptry bulb membrane and knockdown of PfCERLI1 inhibits merozoite invasion. While schizogony and merozoite organelle biogenesis appear normal, biochemical techniques and semi-quantitative superresolution microscopy show that PfCERLI1 knockdown prevents secretion of key rhoptry antigens that coordinate merozoite invasion. PfCERLI1 is a rhoptry associated protein identified to have a direct role in function of this essential merozoite invasion organelle, which has broader implications for understanding apicomplexan invasion biology.

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“…The process of invasion requires a host of proteins to be secreted from its apical organelles including rhoptry bodies and micronemes, among others, and is precisely coordinated. The parasite initially aligns the merozoite apical region toward the host erythrocyte and forms a tight junction at the apex, progressing as the moving junction (MJ) pushes the parasite into the erythrocyte, with the erythrocyte surface forming a ring around the engorged parasite, which would later become the parasitophorous vacuolar membrane (PVM) [25].…”

Section: Invasion/egressmentioning

confidence: 99%

Protein-Protein Interactions in Malaria: Emerging Arena for Future Chemotherapeutics

Pasupureddy¹,

Seshadri²,

Dixit³

et al. 2020

Parasitology and Microbiology Research

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Malaria is one of the most deadly diseases infecting humans. Advances in elimination and vector control have reduced the global malaria burden in the past decade; however, the emerging threat of drug resistance and suboptimal vaccine efficacies threaten global eradication efforts. Unlocking novel drug and vaccine targets while simultaneously mitigating spread of resistant strains seems to be the need of the hour. Protein-protein interactions (PPIs), an integral part of hostpathogen cross-talk and parasite survival, have only recently emerged as promising drug targets. Large PPI networks (interactome) are being developed to better our understanding of various parasite biochemical pathways. In this chapter, we throw light on several newly characterized protein-protein interactions between the host (humans) and parasite (plasmodium) in key processes such as hemoglobin degradation, enzyme regulation, protein export, egress, invasion, and drug resistance and further discuss their viability for development as novel chemotherapeutic targets.

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Targeting malaria parasite invasion of red blood cells as an antimalarial strategy

Cited by 74 publications

References 202 publications

Retargeting azithromycin analogues to have dual-modality antimalarial activity

Retargeting azithromycin analogues to have dual-modality antimalarial activity

PfCERLI1 is a conserved rhoptry associated protein essential for Plasmodium falciparum merozoite invasion of erythrocytes

Protein-Protein Interactions in Malaria: Emerging Arena for Future Chemotherapeutics

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