{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T13:29:07Z","timestamp":1791898147913,"version":"4.3.4"},"reference-count":73,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2023,5,3]],"date-time":"2023-05-03T00:00:00Z","timestamp":1683072000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000060","name":"NIH\/NIAID","doi-asserted-by":"publisher","award":["AI115178"],"award-info":[{"award-number":["AI115178"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000060","name":"NIH\/NIAID","doi-asserted-by":"publisher","award":["GM136211"],"award-info":[{"award-number":["GM136211"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]},{"name":"NIH\/NIGMS","award":["AI115178"],"award-info":[{"award-number":["AI115178"]}]},{"name":"NIH\/NIGMS","award":["GM136211"],"award-info":[{"award-number":["GM136211"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Microorganisms"],"abstract":"<jats:p>Malaria, caused by Plasmodium protozoal parasites, remains a leading cause of morbidity and mortality. The Plasmodium parasite has a complex life cycle, with asexual and sexual forms in humans and Anopheles mosquitoes. Most antimalarials target only the symptomatic asexual blood stage. However, to ensure malaria eradication, new drugs with efficacy at multiple stages of the life cycle are necessary. We previously demonstrated that arsinothricin (AST), a newly discovered organoarsenical natural product, is a potent broad-spectrum antibiotic that inhibits the growth of various prokaryotic pathogens. Here, we report that AST is an effective multi-stage antimalarial. AST is a nonproteinogenic amino acid analog of glutamate that inhibits prokaryotic glutamine synthetase (GS). Phylogenetic analysis shows that Plasmodium GS, which is expressed throughout all stages of the parasite life cycle, is more closely related to prokaryotic GS than eukaryotic GS. AST potently inhibits Plasmodium GS, while it is less effective on human GS. Notably, AST effectively inhibits both Plasmodium erythrocytic proliferation and parasite transmission to mosquitoes. In contrast, AST is relatively nontoxic to a number of human cell lines, suggesting that AST is selective against malaria pathogens, with little negative effect on the human host. We propose that AST is a promising lead compound for developing a new class of multi-stage antimalarials.<\/jats:p>","DOI":"10.3390\/microorganisms11051195","type":"journal-article","created":{"date-parts":[[2023,5,4]],"date-time":"2023-05-04T01:33:36Z","timestamp":1683164016000},"page":"1195","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Arsinothricin Inhibits Plasmodium falciparum Proliferation in Blood and Blocks Parasite Transmission to Mosquitoes"],"prefix":"10.3390","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7243-1761","authenticated-orcid":false,"given":"Masafumi","family":"Yoshinaga","sequence":"first","affiliation":[{"name":"Department of Cellular Biology and Pharmacology, Herbert Wertheim College of Medicine, Florida International University, 11200 SW 8th St., Miami, FL 33199, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guodong","family":"Niu","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, College of Arts, Sciences & Education, Florida International University, 11200 SW 8th St., Miami, FL 33199, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kunie","family":"Yoshinaga-Sakurai","sequence":"additional","affiliation":[{"name":"Department of Cellular Biology and Pharmacology, Herbert Wertheim College of Medicine, Florida International University, 11200 SW 8th St., Miami, FL 33199, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Venkadesh S.","family":"Nadar","sequence":"additional","affiliation":[{"name":"Department of Cellular Biology and Pharmacology, Herbert Wertheim College of Medicine, Florida International University, 11200 SW 8th St., Miami, FL 33199, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaohong","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, College of Arts, Sciences & Education, Florida International University, 11200 SW 8th St., Miami, FL 33199, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5230-4271","authenticated-orcid":false,"given":"Barry P.","family":"Rosen","sequence":"additional","affiliation":[{"name":"Department of Cellular Biology and Pharmacology, Herbert Wertheim College of Medicine, Florida International University, 11200 SW 8th St., Miami, FL 33199, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2121-3393","authenticated-orcid":false,"given":"Jun","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, College of Arts, Sciences & Education, Florida International University, 11200 SW 8th St., Miami, FL 33199, USA"},{"name":"Biomolecular Sciences Institute, Florida International University, Miami, FL 33199, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,5,3]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Monroe, A., Williams, N.A., Ogoma, S., Karema, C., and Okumu, F. (2022). Reflections on the 2021 World Malaria Report and the future of malaria control. Malar. J., 21.","DOI":"10.1186\/s12936-022-04178-7"},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Nadeem, A.Y., Shehzad, A., Islam, S.U., Al-Suhaimi, E.A., and Lee, Y.S. (2022). Mosquirix\u2122 RTS, S\/AS01 Vaccine Development, Immunogenicity, and Efficacy. Vaccines, 10.","DOI":"10.3390\/vaccines10050713"},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Piameu, M., Nwane, P., Toussile, W., Mavridis, K., Wipf, N.C., Kouadio, P.F., Mbakop, L.R., Mandeng, S., Ekoko, W.E., and Toto, J.C. (2021). Pyrethroid and Etofenprox Resistance in Anopheles gambiae and Anopheles coluzzii from Vegetable Farms in Yaound\u00e9, Cameroon: Dynamics, Intensity and Molecular Basis. Molecules, 26.","DOI":"10.3390\/molecules26185543"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1038\/s41564-018-0214-7","article-title":"Vector biology meets disease control: Using basic research to fight vector-borne diseases","volume":"4","author":"Shaw","year":"2019","journal-title":"Nat. Microbiol."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Chidimatembue, A., Svigel, S.S., Mayor, A., A\u00edde, P., Nhama, A., Nhamussua, L., Nhacolo, A., Bassat, Q., Salvador, C., and Enosse, S. (2021). Molecular surveillance for polymorphisms associated with artemisinin-based combination therapy resistance in Plasmodium falciparum isolates collected in Mozambique, 2018. Malar. J., 20.","DOI":"10.1186\/s12936-021-03930-9"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1163","DOI":"10.1056\/NEJMoa2101746","article-title":"Evidence of Artemisinin-Resistant Malaria in Africa","volume":"385","author":"Balikagala","year":"2021","journal-title":"N. Engl. J. Med."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1038\/s41586-019-0973-1","article-title":"Exposing Anopheles mosquitoes to antimalarials blocks Plasmodium parasite transmission","volume":"567","author":"Paton","year":"2019","journal-title":"Nature"},{"key":"ref_8","first-page":"52","article-title":"Antimalarial natural products: A review","volume":"2","author":"Mojab","year":"2012","journal-title":"Avicenna. J. Phytomed."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"629","DOI":"10.1021\/acs.jnatprod.5b01055","article-title":"Natural Products as Sources of New Drugs from 1981 to 2014","volume":"79","author":"Newman","year":"2016","journal-title":"J. Nat. Prod."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Niu, G., Annamalai, T., Wang, X., Li, S., Munga, S., Niu, G., Tse-Dinh, Y.C., and Li, J. (2020). A diverse global fungal library for drug discovery. PeerJ, 8.","DOI":"10.7717\/peerj.10392"},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Niu, G., Hao, Y., Wang, X., Gao, J.M., and Li, J. (2020). Fungal Metabolite Asperaculane B Inhibits Malaria Infection and Transmission. Molecules, 25.","DOI":"10.3390\/molecules25133018"},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Niu, G., Wang, B., Zhang, G., King, J.B., Cichewicz, R.H., and Li, J. (2015). Targeting mosquito FREP1 with a fungal metabolite blocks malaria transmission. Sci. Rep., 5.","DOI":"10.1038\/srep14694"},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Niu, G., Wang, X., Hao, Y., Kandel, S., Niu, G., Raptis, R.G., and Li, J. (2021). A novel fungal metabolite inhibits Plasmodium falciparum transmission and infection. Parasit. Vectors, 14.","DOI":"10.1186\/s13071-021-04677-7"},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Niu, G., Kalani, K., Wang, X., and Li, J. (2021). Sterigmatocystin Limits Plasmodium falciparum Proliferation and Transmission. Pharmaceuticals, 14.","DOI":"10.3390\/ph14121238"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"3047","DOI":"10.4155\/fmc-2019-0225","article-title":"Recent advances in transmission-blocking drugs for malaria elimination","volume":"11","author":"Wadi","year":"2019","journal-title":"Future Med. Chem."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Kuramata, M., Sakakibara, F., Kataoka, R., Yamazaki, K., Baba, K., Ishizaka, M., Hiradate, S., Kamo, T., and Ishikawa, S. (2016). Arsinothricin, a novel organoarsenic species produced by a rice rhizosphere bacterium. Environ. Chem., 13.","DOI":"10.1071\/EN14247"},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Nadar, V.S., Chen, J., Dheeman, D.S., Galv\u00e1n, A.E., Yoshinaga-Sakurai, K., Kandavelu, P., Sankaran, B., Kuramata, M., Ishikawa, S., and Rosen, B.P. (2019). Arsinothricin, an arsenic-containing non-proteinogenic amino acid analog of glutamate, is a broad-spectrum antibiotic. Commun. Biol., 2.","DOI":"10.1038\/s42003-019-0365-y"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"318","DOI":"10.1016\/S1473-3099(17)30753-3","article-title":"Discovery, research, and development of new antibiotics: The WHO priority list of antibiotic-resistant bacteria and tuberculosis","volume":"18","author":"Tacconelli","year":"2018","journal-title":"Lancet Infect. Dis."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"283","DOI":"10.1007\/s10534-022-00371-y","article-title":"Arsenic in medicine: Past, present and future","volume":"36","author":"Paul","year":"2022","journal-title":"Biometals"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"719","DOI":"10.1007\/s00277-013-1707-3","article-title":"The evolving use of arsenic in pharmacotherapy of malignant disease","volume":"92","author":"Kritharis","year":"2013","journal-title":"Ann. Hematol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"148","DOI":"10.1016\/S0140-6736(09)60829-1","article-title":"Human African trypanosomiasis","volume":"375","author":"Brun","year":"2010","journal-title":"Lancet"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1016\/j.envres.2017.12.012","article-title":"Trends in urinary arsenic among the U.S. population by drinking water source: Results from the National Health and Nutritional Examinations Survey 2003\u20132014","volume":"162","author":"Welch","year":"2018","journal-title":"Environ. Res."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"556","DOI":"10.1016\/j.cell.2017.01.029","article-title":"Poisoning the Devil","volume":"168","author":"Chen","year":"2017","journal-title":"Cell"},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Galv\u00e1n, A.E., Paul, N.P., Chen, J., Yoshinaga-Sakurai, K., Utturkar, S.M., Rosen, B.P., and Yoshinaga, M. (2021). Identification of the Biosynthetic Gene Cluster for the Organoarsenical Antibiotic Arsinothricin. Microbiol. Spectr., 9.","DOI":"10.1128\/Spectrum.00502-21"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"411","DOI":"10.1021\/es60052a005","article-title":"Simultaneous determination of arsenate and phosphate in natural waters","volume":"5","author":"Johnson","year":"1971","journal-title":"Environ. Sci. Technol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"2809","DOI":"10.1021\/acs.jnatprod.0c00522","article-title":"Semisynthesis of the Organoarsenical Antibiotic Arsinothricin","volume":"83","author":"Suzol","year":"2020","journal-title":"J. Nat. Prod."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"616","DOI":"10.1021\/tx700038x","article-title":"Arsenic metabolism and thioarsenicals in hamsters and rats","volume":"20","author":"Naranmandura","year":"2007","journal-title":"Chem. Res. Toxicol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1010","DOI":"10.1021\/tx060053f","article-title":"Trivalent arsenicals are bound to proteins during reductive methylation","volume":"19","author":"Naranmandura","year":"2006","journal-title":"Chem. Res. Toxicol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"20675","DOI":"10.1073\/pnas.1321024110","article-title":"Genome-block expression-assisted association studies discover malaria resistance genes in Anopheles gambiae","volume":"110","author":"Li","year":"2013","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"16490","DOI":"10.1074\/jbc.M114.623165","article-title":"Anopheles Midgut FREP1 Mediates Plasmodium Invasion","volume":"290","author":"Zhang","year":"2015","journal-title":"J. Biol. Chem."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"958","DOI":"10.1016\/j.jff.2014.12.023","article-title":"The anti-atherogenic effects of eicosapentaenoic and docosahexaenoic acid are dependent on the stage of THP-1 macrophage differentiation","volume":"19","author":"McCartan","year":"2015","journal-title":"J. Funct. Foods"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"605","DOI":"10.1111\/evo.14434","article-title":"Glutamine synthetase evolutionary history revisited: Tracing back beyond the Last Universal Common Ancestor","volume":"76","year":"2022","journal-title":"Evolution"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"R836","DOI":"10.1016\/j.cub.2019.07.047","article-title":"Evolution: Parallel Paths to Parasitism in the Apicomplexa","volume":"29","author":"Rueckert","year":"2019","journal-title":"Curr. Biol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"3022","DOI":"10.1093\/molbev\/msab120","article-title":"MEGA11: Molecular Evolutionary Genetics Analysis Version 11","volume":"38","author":"Tamura","year":"2021","journal-title":"Mol. Biol. Evol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1229","DOI":"10.1093\/molbev\/mst012","article-title":"Building phylogenetic trees from molecular data with MEGA","volume":"30","author":"Hall","year":"2013","journal-title":"Mol. Biol. Evol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"4673","DOI":"10.1093\/nar\/22.22.4673","article-title":"CLUSTAL W: Improving the sensitivity of progressive multiple sequence alignment through sequence weighting, position-specific gap penalties and weight matrix choice","volume":"22","author":"Thompson","year":"1994","journal-title":"Nucleic. Acids. Res."},{"key":"ref_37","first-page":"406","article-title":"The neighbor-joining method: A new method for reconstructing phylogenetic trees","volume":"4","author":"Saitou","year":"1987","journal-title":"Mol. Biol. Evol."},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Sievers, F., Wilm, A., Dineen, D., Gibson, T.J., Karplus, K., Li, W., Lopez, R., McWilliam, H., Remmert, M., and S\u00f6ding, J. (2011). Fast, scalable generation of high-quality protein multiple sequence alignments using Clustal Omega. Mol. Syst. Biol., 7.","DOI":"10.1038\/msb.2011.75"},{"key":"ref_39","unstructured":"Sambrook, J., Fritsch, E.F., and Maniatis, T. (1989). Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Laboratory Press. [2nd ed.]."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1038\/bjc.1987.190","article-title":"A study of some variables in a tetrazolium dye (MTT) based assay for cell growth and chemosensitivity","volume":"56","author":"Twentyman","year":"1987","journal-title":"Br. J. Cancer"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1038\/s41592-019-0637-y","article-title":"Bottom-up structural proteomics: CryoEM of protein complexes enriched from the cellular milieu","volume":"17","author":"Ho","year":"2020","journal-title":"Nat. Methods"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"2785","DOI":"10.1002\/jcc.21256","article-title":"AutoDock4 and AutoDockTools4: Automated docking with selective receptor flexibility","volume":"30","author":"Morris","year":"2009","journal-title":"J. Comput. Chem."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1016\/j.jmb.2007.10.029","article-title":"Crystal structures of mammalian glutamine synthetases illustrate substrate-induced conformational changes and provide opportunities for drug and herbicide design","volume":"375","author":"Krajewski","year":"2008","journal-title":"J. Mol. Biol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"D539-43","DOI":"10.1093\/nar\/gkn814","article-title":"PlasmoDB: A functional genomic database for malaria parasites","volume":"37","author":"Aurrecoechea","year":"2009","journal-title":"Nucleic. Acids Res."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"424","DOI":"10.1016\/j.bbrc.2006.09.062","article-title":"Structural and functional properties of lengsin, a pseudo-glutamine synthetase in the transparent human lens","volume":"350","author":"Grassi","year":"2006","journal-title":"Biochem. Biophys Res. Commun."},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"G\u00f3mez-D\u00edaz, E., Yerbanga, R.S., Lef\u00e8vre, T., Cohuet, A., Rowley, M.J., Ouedraogo, J.B., and Corces, V.G. (2017). Epigenetic regulation of Plasmodium falciparum clonally variant gene expression during development in Anopheles gambiae. Sci. Rep., 7.","DOI":"10.1038\/srep40655"},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"L\u00f3pez-Barrag\u00e1n, M.J., Lemieux, J., Qui\u00f1ones, M., Williamson, K.C., Molina-Cruz, A., Cui, K., Barillas-Mury, C., Zhao, K., and Su, X.Z. (2011). Directional gene expression and antisense transcripts in sexual and asexual stages of Plasmodium falciparum. BMC Genom., 12.","DOI":"10.1186\/1471-2164-12-587"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1503","DOI":"10.1126\/science.1087025","article-title":"Discovery of gene function by expression profiling of the malaria parasite life cycle","volume":"301","author":"Zhou","year":"2003","journal-title":"Science"},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"Counihan, N.A., Modak, J.K., and de Koning-Ward, T.F. (2021). How Malaria Parasites Acquire Nutrients From Their Host. Front. Cell. Dev. Biol., 9.","DOI":"10.3389\/fcell.2021.649184"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"14378","DOI":"10.1073\/pnas.1009198107","article-title":"Isolation of viable Plasmodium falciparum merozoites to define erythrocyte invasion events and advance vaccine and drug development","volume":"107","author":"Boyle","year":"2010","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"931","DOI":"10.3109\/14756366.2015.1070846","article-title":"Bisphosphonic acids as effective inhibitors of Mycobacterium tuberculosis glutamine synthetase","volume":"31","author":"Kosikowska","year":"2016","journal-title":"J. Enzyme Inhib Med. Chem."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1016\/j.pt.2007.02.004","article-title":"Metabolism of Leishmania: Proven and predicted","volume":"23","author":"Opperdoes","year":"2007","journal-title":"Trends Parasitol."},{"key":"ref_53","doi-asserted-by":"crossref","unstructured":"Saunders, E.C., Ng, W.W., Kloehn, J., Chambers, J.M., Ng, M., and McConville, M.J. (2014). Induction of a stringent metabolic response in intracellular stages of Leishmania mexicana leads to increased dependence on mitochondrial metabolism. PLoS Pathog., 10.","DOI":"10.1371\/journal.ppat.1003888"},{"key":"ref_54","doi-asserted-by":"crossref","unstructured":"Magdaleno, A., Su\u00e1rez Mantilla, B., Rocha, S.C., Pral, E.M., and Silber, A.M. (2011). The Involvement of Glutamate Metabolism in the Resistance to Thermal, Nutritional, and Oxidative Stress in Trypanosoma cruzi. Enzyme. Res., 2011.","DOI":"10.4061\/2011\/486928"},{"key":"ref_55","doi-asserted-by":"crossref","unstructured":"Kumar, V., Ghosh, S., Roy, K., Pal, C., and Singh, S. (2021). Deletion of Glutamine Synthetase Gene Disrupts the Survivability and Infectivity of Leishmania donovani. Front. Cell. Infect. Microbiol., 11.","DOI":"10.3389\/fcimb.2021.622266"},{"key":"ref_56","doi-asserted-by":"crossref","unstructured":"Crispim, M., Damasceno, F.S., Hern\u00e1ndez, A., Baris\u00f3n, M.J., Pretto Sauter, I., Souza Pavani, R., Santos Moura, A., Pral, E.M.F., Cortez, M., and Elias, M.C. (2018). The glutamine synthetase of Trypanosoma cruzi is required for its resistance to ammonium accumulation and evasion of the parasitophorous vacuole during host-cell infection. PLoS Negl. Trop. Dis., 12.","DOI":"10.1371\/journal.pntd.0006170"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"1291","DOI":"10.1016\/j.bcp.2009.12.025","article-title":"Inhibition of Plasmodium falciparum pH regulation by small molecule indole derivatives results in rapid parasite death","volume":"79","author":"Chan","year":"2010","journal-title":"Biochem. Pharmacol."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1007\/978-1-4939-9857-9_2","article-title":"ToxoDB: Functional Genomics Resource for Toxoplasma and Related Organisms","volume":"2071","author":"Harb","year":"2020","journal-title":"Methods Mol. Biol."},{"key":"ref_59","doi-asserted-by":"crossref","unstructured":"Guiton, P.S., Sagawa, J.M., Fritz, H.M., and Boothroyd, J.C. (2017). An in vitro model of intestinal infection reveals a developmentally regulated transcriptome of Toxoplasma sporozoites and a NF-\u03baB-like signature in infected host cells. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0173018"},{"key":"ref_60","doi-asserted-by":"crossref","unstructured":"Ramakrishnan, C., Maier, S., Walker, R.A., Rehrauer, H., Joekel, D.E., Winiger, R.R., Basso, W.U., Grigg, M.E., Hehl, A.B., and Deplazes, P. (2019). An experimental genetically attenuated live vaccine to prevent transmission of Toxoplasma gondii by cats. Sci. Rep., 9.","DOI":"10.1038\/s41598-018-37671-8"},{"key":"ref_61","doi-asserted-by":"crossref","unstructured":"Fritz, H.M., Buchholz, K.R., Chen, X., Durbin-Johnson, B., Rocke, D.M., Conrad, P.A., and Boothroyd, J.C. (2012). Transcriptomic analysis of toxoplasma development reveals many novel functions and structures specific to sporozoites and oocysts. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0029998"},{"key":"ref_62","doi-asserted-by":"crossref","unstructured":"Behnke, M.S., Zhang, T.P., Dubey, J.P., and Sibley, L.D. (2014). Toxoplasma gondii merozoite gene expression analysis with comparison to the life cycle discloses a unique expression state during enteric development. BMC Genom., 15.","DOI":"10.1186\/1471-2164-15-350"},{"key":"ref_63","doi-asserted-by":"crossref","unstructured":"Walker, R.A., Sharman, P.A., Miller, C.M., Lippuner, C., Okoniewski, M., Eichenberger, R.M., Ramakrishnan, C., Brossier, F., Deplazes, P., and Hehl, A.B. (2015). RNA Seq analysis of the Eimeria tenella gametocyte transcriptome reveals clues about the molecular basis for sexual reproduction and oocyst biogenesis. BMC Genom., 16.","DOI":"10.1186\/s12864-015-1298-6"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"1676","DOI":"10.1101\/gr.168955.113","article-title":"Genomic analysis of the causative agents of coccidiosis in domestic chickens","volume":"24","author":"Reid","year":"2014","journal-title":"Genome. Res."},{"key":"ref_65","doi-asserted-by":"crossref","unstructured":"Ehret, T., Spork, S., Dieterich, C., Lucius, R., and Heitlinger, E. (2017). Dual RNA-seq reveals no plastic transcriptional response of the coccidian parasite Eimeria falciformis to host immune defenses. BMC Genom., 18.","DOI":"10.1186\/s12864-017-4095-6"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"D419-22","DOI":"10.1093\/nar\/gkj078","article-title":"CryptoDB: A Cryptosporidium bioinformatics resource update","volume":"34","author":"Heiges","year":"2006","journal-title":"Nucleic. Acids Res."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"2226","DOI":"10.1038\/s41564-019-0539-x","article-title":"Life cycle progression and sexual development of the apicomplexan parasite Cryptosporidium parvum","volume":"4","author":"Tandel","year":"2019","journal-title":"Nat. Microbiol."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"1089","DOI":"10.1038\/nbt0905-1089","article-title":"Protozoan genomics for drug discovery","volume":"23","author":"Chaudhary","year":"2005","journal-title":"Nat. Biotechnol."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"468","DOI":"10.1016\/j.pt.2008.07.004","article-title":"Apicomplexan mitochondrial metabolism: A story of gains, losses and retentions","volume":"24","author":"Seeber","year":"2008","journal-title":"Trends Parasitol."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"eaap7847","DOI":"10.1126\/science.aap7847","article-title":"Uncovering the essential genes of the human malaria parasite Plasmodium falciparum by saturation mutagenesis","volume":"360","author":"Zhang","year":"2018","journal-title":"Science"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1124\/molpharm.120.000186","article-title":"How Physiologic Targets Can Be Distinguished from Drug-Binding Proteins","volume":"100","year":"2021","journal-title":"Mol. Pharmacol."},{"key":"ref_72","doi-asserted-by":"crossref","unstructured":"Yang, J., He, Y., Li, Y., Zhang, X., Wong, Y.K., Shen, S., Zhong, T., Zhang, J., Liu, Q., and Wang, J. (2020). Advances in the research on the targets of anti-malaria actions of artemisinin. Pharmacol. Ther., 216.","DOI":"10.1016\/j.pharmthera.2020.107697"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"905","DOI":"10.1111\/cmi.12604","article-title":"The development of malaria parasites in the mosquito midgut","volume":"18","author":"Bennink","year":"2016","journal-title":"Cell. Microbiol."}],"container-title":["Microorganisms"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-2607\/11\/5\/1195\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T19:28:45Z","timestamp":1760124525000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-2607\/11\/5\/1195"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,5,3]]},"references-count":73,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2023,5]]}},"alternative-id":["microorganisms11051195"],"URL":"https:\/\/doi.org\/10.3390\/microorganisms11051195","relation":{},"ISSN":["2076-2607"],"issn-type":[{"value":"2076-2607","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,5,3]]}}}