Autophagy Underlies the Proteostasis Mechanisms of Artemisinin Resistance in P. falciparum Malaria

Ray, Ananya; Mathur, Miti; Choubey, Deepak; Karmodiya, Krishanpal; Surolia, Namita

doi:10.1128/mbio.00630-22

Cited by 14 publications

(23 citation statements)

References 83 publications

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“…Here, we observed improved parasite survival following limitation of single nutrients in in vitro growth media; hypoxanthine and thiamine were chosen in part due to contrasting metabolic attributes outlined in the Results section, but also due to potential relevance to conditions P. falciparum may experience in vivo (see further discussion below). This approach is similar to other studies that induced nutrient stress by reduction of a single amino acid 44,45 or select metabolite classes 24,31,46 . We also observed the survival boost when parasites were grown in HPLM, a physiological media formulation that has reduced concentrations of multiple nutrients 13 .…”

Section: Discussionmentioning

confidence: 81%

“…Further, polymorphisms in autophagy-related genes, such as ATG18 and ATG7, are associated with decreased artemisinin sensitivity in Southeast Asian parasite populations 29,30 . Recent evidence indicates the role of eIF2α phosphorylation in promoting autophagy is conserved in Plasmodium 31 . Thus, autophagy may be activated by our metabolic priming in a manner associated with DHA survival.…”

Section: Resultsmentioning

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%

“…4 (ATG8), Fig. 5C (only Hypoxanthine priming), grey text-full contribution to phenotype remains unclear due to the contribution of autophagy to DHA recovery 29,31 , Supplemental Fig. 4.…”

Section: Tables and Figures Tablementioning

confidence: 99%

“…STK2, STK, CDPK, ARK3), Supplemental Table 2 "Phospho_mero" (482 genes); Vesicular trafficking: Table2(i.e. coronin); Autophagy: Supplemental Fig.4(ATG8), Fig.5C(only Hypoxanthine priming), grey text-full contribution to phenotype remains unclear due to the contribution of autophagy to DHA recovery29,31 , Supplemental Fig.4. C) Previous studies identified pathways associated with artemisinin tolerance.…”

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confidence: 99%

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Nutrient limitation mimics artemisinin tolerance in malaria

Brown

Warthan

Aryal

et al. 2022

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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: 81%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

“…4 (ATG8), Fig. 5C (only Hypoxanthine priming), grey text-full contribution to phenotype remains unclear due to the contribution of autophagy to DHA recovery 29,31 , Supplemental Fig. 4.…”

Section: Tables and Figures Tablementioning

confidence: 99%

mentioning

confidence: 99%

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Nutrient limitation mimics artemisinin tolerance in malaria

Brown

Warthan

Aryal

et al. 2022

Preprint

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Transition Metal Complexes as Antimalarial Agents: A Review

et al. 2023

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In antimalarial drug development research, overcoming drug resistance has been a major challenge for researchers. Nowadays, several drugs like chloroquine, mefloquine, sulfadoxine, and artemisinin are used to treat malaria. But increment in drug resistance has pushed researchers to find novel drugs to tackle drug resistance problems. The idea of using transition metal complexes with pharmacophores as ligands/ligand pendants to show enhanced antimalarial activity with a novel mechanism of action has gained significant attention recently. The advantages of metal complexes include tunable chemical/physical properties, redox activity, avoiding resistance factors, etc. Several recent reports have successfully demonstrated that the metal complexation of known organic antimalarial drugs can overcome drug resistance by showing enhanced activities than the parent drugs. This review has discussed the fruitful research works done in the past few years falling into this criterion. Based on transition metal series (3d, 4d, or 5d), the antimalarial metal complexes have been divided into three broad categories (3d, 4d, or 5d metal‐based), and their activities have been compared with the similar control complexes as well as the parent drugs. Furthermore, we have also commented on the potential issues and their possible solution for translating these metal‐based antimalarial complexes into the clinic.

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