Artemisinin resistance in the malaria parasite, Plasmodium falciparum, originates from its initial transcriptional response

Zhu, Lei; Pluijm, Rob W van der; Kucharski, Michal; Nayak, Sourav; Tripathi, Jaishree; White, Nicholas J.; Day, Nicholas P. J.; Faiz, Abul; Phyo, Aung Pyae; Amaratunga, Chanaki; Lek, Dysoley; Ashley, Elizabeth A.; Nosten, François; Smithuis, Frank; Ginsburg, Hagaï; Seidlein, Lorenz von; Lin, Khin; Imwong, Mallika; Chotivanich, Kesinee; Mayxay, Mayfong; Dhorda, Mehul; Nguyen, Hoang Chau; Nguyen, Thuy; Miotto, Olivo; Newton, Paul N.; Jittamala, Podjanee; Tripura, Rupam; Pukrittayakamee, Sasithon; Peto, Thomas J.; Hien, Tran Tinh; Dondorp, Arjen M.; Bozdech, Zbynek

doi:10.1038/s42003-022-03215-0

Cited by 39 publications

(64 citation statements)

References 75 publications

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“…Future investigations should determine the longevity of priming-induced pro-survival signals and whether this adaptation facilitates development of genetic tolerance. This phenomenon has been observed in the development of antibiotic resistant bacteria 47 and recently proposed for clinical Plasmodium artemisinin resistance 38 . Of note, more than half of the top transcriptional markers for resistance identified by Zhu, et al .…”

Section: Discussionmentioning

confidence: 77%

“…protein-protein interactions between P. falciparum and the red blood cell). Upregulation of exported proteins has been previously observed in both the artemisinin resistance transcriptome and as a response to nutrient limitation 36–38 . Translational regulation was also significantly upregulated in all three conditions in concordance with previous knowledge of the eIF2α-mediated response under nutrient stress ( Fig.…”

Section: Resultsmentioning

confidence: 90%

Section: Molecular Connections Between Nutrient Limitation and Dha Su...mentioning

confidence: 77%

“…This phenomenon has been observed in the development of antibiotic resistant bacteria 48 and recently proposed for Plasmodium artemisinin tolerance by Zhu, et al . 38 . Of note, more than half of the top transcriptional markers for resistance identified by Zhu, et al .…”

Section: Discussionmentioning

confidence: 99%

“…C ) Previous studies identified pathways associated with artemisinin tolerance. Vesicular trafficking: kelch13 28 , coronon 39 , Ap2μ 59 ; Autophagy: ATG18 29,31 ; Translational regulation: unfolded protein response 60 , proteasomal degradation (UBP1 59 ); Exported proteins 36,38 ; Invasion: GLURP and Phil1 40 ; Kinome: STK2, STK, CDPK 40 , Latency: grey text-unclear if distinct from nutrient-dependent latency or directly contributes to tolerance 25,61 .…”

Section: Discussionmentioning

confidence: 99%

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Nutrient limitation mimics artemisinin tolerance in malaria

Brown

Warthan

Aryal

et al. 2022

Preprint

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Mounting evidence demonstrates that nutritional environment can alter pathogen drug sensitivity. While the nutrient-rich media used for standard in vitro culture contains supra-physiological nutrient concentrations, pathogens encounter a relatively restrictive environment in vivo. We assessed the effect of nutrient limitation on the protozoan parasite that causes malaria and demonstrated that short-term growth under physiologically-relevant mild nutrient stress (or metabolic priming) triggers increased tolerance of the potent antimalarial drug dihydroartemisinin (DHA). We observed beneficial effects using both short-term survival assays and longer-term proliferation studies, where metabolic priming increases parasite survival to a level previously defined as DHA resistant (>1% survival). We performed these assessments by either decreasing single nutrients that have distinct roles in parasite metabolism or using a media formulation with reductions in many nutrients that simulates the human plasma environment. We determined that priming-induced DHA tolerance was restricted to parasites that had newly invaded the host red blood cell but the effect was not dependent on genetic background. The molecular mechanisms of this intrinsic effect mimic aspects of genetic artemisinin tolerance, including translational repression, autophagy, and protein export. This finding suggests regardless of the impact on survival rates, environmental stress could stimulate changes that ultimately directly contribute to drug tolerance. Because metabolic stress is likely to occur more frequently in vivo compared to the stable in vitro environment, priming-induced drug tolerance has ramifications for how in vitro results translate to in vivo studies. Improving our understanding of how pathogens adjust their metabolism to impact survival of current and future drugs is an important avenue of research to prevent and slow the spread of resistance.

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Section: Discussionmentioning

confidence: 77%

Section: Resultsmentioning

confidence: 90%

Section: Molecular Connections Between Nutrient Limitation and Dha Su...mentioning

confidence: 77%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 3 more Smart Citations

Nutrient limitation mimics artemisinin tolerance in malaria

Brown

Warthan

Aryal

et al. 2022

Preprint

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Synthesis and in vitro antiprotozoal evaluation of novel metronidazole–Schiff base hybrids

Beteck

Isaacs

Legoabe

et al. 2022

Archiv der Pharmazie

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Herein we report the synthesis of 21 novel small molecules inspired by metronidazole and Schiff base compounds. The compounds were evaluated against Trichomonas vaginalis and cross-screened against other pathogenic protozoans of clinical relevance. Most of these compounds were potent against T. vaginalis, exhibiting IC 50 values < 5 µM. Compound 20, the most active compound against T. vaginalis, exhibited an IC 50 value of 3.4 µM. A few compounds also exhibited activity against Plasmodium falciparum and Trypanosomal brucei brucei, with compound 6 exhibiting an IC 50 value of 0.7 µM against P. falciparum and compound 22 exhibiting an IC 50 value of 1.4 µM against T.b. brucei. Compound 22 is a broad-spectrum antiprotozoal agent, showing activities against all three pathogenic protozoans under investigation.

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