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Identifying Fast and Slow-Acting Antimalarial Compounds of Pandemic Response Box Against Blood-Stage Culture of Plasmodium falciparum 3D7

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Abstract

The evolving clinical resistance in Plasmodium falciparum and the spike in malarial cases after the COVID-19 outbreak has triggered a search for new antimalarials effective against multi-drug-resistant P. falciparum strains. In this study, we assessed the timing of action, either fast or slow-acting of 13 potent compounds of Pandemic Response Box (PRB) against blood-stage Pf3D7 strain by SYBR Green-I assay. The asynchronous culture of Pf3D7 was exposed to varying concentrations of 13 compounds, and IC50 values were determined at 12, 24, 48, 72, and 96 h. We identified four fast-acting compounds (MMV000008, MMV1593541, MMV020752, MMV396785) with rapid-growth inhibitory activity having IC50 values ≤ 0.3 µM at 12 and 24 h. Similarly, we determined nine slow-acting compounds (MMV159340, MMV1634492, MMV1581558, MMV689758, MMV1593540, MMV394033, MMV019724, MMV000725, MMV1557856) having IC50 values ≤ 0.5 µM at 72 and 96 h. Furthermore, the stage-specific action of the two most potent fast-acting compounds (MMV1593541 and MMV020752) against rings, trophozoites, and schizonts at 48 h of exposure revealed that ring-stage parasites showed reduced IC50 values compared to mature stage forms. Therefore, our study demonstrates for the first time the identification of the most potent fast and slow-acting compounds from PRB against blood-stage infection, suggesting its utility in clinics and considering it as a partner drug in combination therapies.

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References

  1. Mbacham WF et al (2019) Current situation of malaria in Africa. Methods Mol Biol 2013:29–44

    Article  PubMed  CAS  Google Scholar 

  2. Kumar A et al (2012) Malaria in South Asia: prevalence and control. Acta Trop 121(3):246–255

    Article  PubMed  Google Scholar 

  3. World Health Organization, "World Malaria Report 2023". https://www.who.int/publications/i/item/9789240086173

  4. Escalante AA, Ayala FJ (1995) Evolutionary origin of Plasmodium and other Apicomplexa based on rRNA genes. Proc Natl Acad Sci USA 92(13):5793–5797

    Article  PubMed  PubMed Central  ADS  CAS  Google Scholar 

  5. Schantz-Dunn J, Nour NM (2009) Malaria and pregnancy: a global health perspective. Rev Obstet Gynecol 2(3):186–192

    PubMed  PubMed Central  Google Scholar 

  6. Medana IM, Turner GD (2007) Plasmodium falciparum and the blood-brain barrier–contacts and consequences. J Infect Dis 195(7):921–923

    Article  PubMed  Google Scholar 

  7. Monroe A et al (2022) Reflections on the 2021 World Malaria Report and the future of malaria control. Malar J 21(1):154

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  8. Cheuka PM, Mambwe D, Mayoka G (2023) Medicinal chemistry and target identification of synthetic clinical and advanced preclinical antimalarial candidates (2000–2022). Curr Top Med Chem 23(3):227–247

    Article  PubMed  CAS  Google Scholar 

  9. Tisnerat C et al (2022) Antimalarial drug discovery: from quinine to the most recent promising clinical drug candidates. Curr Med Chem 29(19):3326–3365

    Article  PubMed  CAS  Google Scholar 

  10. Burrows JN et al (2013) Designing the next generation of medicines for malaria control and eradication. Malar J 12:187

    Article  PubMed  PubMed Central  Google Scholar 

  11. Corey VC et al (2016) A broad analysis of resistance development in the malaria parasite. Nat Commun 7:11901

    Article  PubMed  PubMed Central  ADS  CAS  Google Scholar 

  12. Harte PG, De Souza JB, Playfair JH (1982) Failure of malaria vaccination in mice born to immune mothers. Clin Exp Immunol 49(3):509–516

    PubMed  PubMed Central  CAS  Google Scholar 

  13. Butler DJN (2012) Malaria vaccine gives disappointing results

  14. Guilbride DL, Gawlinski P, Guilbride PD (2010) Why functional pre-erythrocytic and bloodstage malaria vaccines fail: a meta-analysis of fully protective immunizations and novel immunological model. PLoS ONE 5(5):e10685

    Article  PubMed  PubMed Central  ADS  Google Scholar 

  15. El-Moamly AA, El-Sweify MA (2023) Malaria vaccines: the 60-year journey of hope and final success-lessons learned and future prospects. Trop Med Health 51(1):29

    Article  PubMed  PubMed Central  Google Scholar 

  16. World Health Organization (2016) Artemisinin and artemisinin-based combination therapy resistance: status report. World Health Organization

  17. Liu Y et al (2022) Molecular surveillance of artemisinin-based combination therapies resistance in plasmodium falciparum parasites from Bioko Island, Equatorial Guinea. Microbiol Spectr 10(3):e0041322

    Article  MathSciNet  PubMed  Google Scholar 

  18. Salam N et al (2018) Global prevalence and distribution of coinfection of malaria, dengue and chikungunya: a systematic review. BMC Public Health 18(1):710

    Article  PubMed  PubMed Central  Google Scholar 

  19. Al Hajjar S, McIntosh K (2010) The first influenza pandemic of the 21st century. Ann Saudi Med 30(1):1–10

    Article  PubMed  PubMed Central  Google Scholar 

  20. Samby K et al (2022) The pandemic response box horizontal line accelerating drug discovery efforts after disease outbreaks. ACS Infect Dis 8(4):713–720

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  21. Payne D (1987) Spread of chloroquine resistance in Plasmodium falciparum. Parasitol Today 3(8):241–246

    Article  PubMed  CAS  Google Scholar 

  22. Dondorp AM et al (2009) Artemisinin resistance in Plasmodium falciparum malaria. New England J Med 361(5):455–467

    Article  CAS  Google Scholar 

  23. Na-Bangchang K et al (2010) Declining in efficacy of a three-day combination regimen of mefloquine-artesunate in a multi-drug resistance area along the Thai-Myanmar border. Malar J 9:273

    Article  PubMed  PubMed Central  Google Scholar 

  24. Spangenberg T et al (2013) The open access malaria box: a drug discovery catalyst for neglected diseases. PLoS ONE 8(6):e62906

    Article  PubMed  PubMed Central  ADS  CAS  Google Scholar 

  25. Veale CGL (2019) Unpacking the pathogen box-an open source tool for fighting neglected tropical disease. ChemMedChem 14(4):386–453

    Article  PubMed  CAS  Google Scholar 

  26. Calit J et al (2018) Screening the pathogen box for molecules active against plasmodium sexual stages using a new nanoluciferase-based transgenic line of P. berghei identifies transmission-blocking compounds. Antimicrob Agents Chemother. https://doi.org/10.1128/AAC.01053-18

    Article  PubMed  PubMed Central  Google Scholar 

  27. Mathew J et al (2022) Malaria box-inspired discovery of N-aminoalkyl-beta-carboline-3-carboxamides, a novel orally active class of antimalarials. ACS Med Chem Lett 13(3):365–370

    Article  MathSciNet  PubMed  PubMed Central  CAS  Google Scholar 

  28. Reader J et al (2021) Multistage and transmission-blocking targeted antimalarials discovered from the open-source MMV pandemic response box. Nat Commun 12(1):269

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  29. Kim T et al (2021) A screening of the MMV pandemic response box reveals epetraborole as a new potent inhibitor against mycobacterium abscessus. Int J Mol Sci. https://doi.org/10.3390/ijms22115936

    Article  PubMed  PubMed Central  Google Scholar 

  30. Macho M et al (2022) Screening of the medicines for malaria venture pandemic response box for discovery of antivirulent drug against pseudomonas aeruginosa. Microbiol Spectr 10(6):e0223222

    Article  PubMed  Google Scholar 

  31. Rice CA et al (2020) Discovery of anti-amoebic inhibitors from screening the MMV pandemic response box on Balamuthia mandrillaris, Naegleria fowleri, and Acanthamoeba castellanii. Pathogens. https://doi.org/10.3390/pathogens9060476

    Article  PubMed  PubMed Central  Google Scholar 

  32. Rollin-Pinheiro R et al (2023) Pandemic response box (R) library as a source of antifungal drugs against Scedosporium and Lomentospora species. PLoS ONE 18(2):e0280964

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  33. Borba-Santos LP et al (2022) Screening of pandemic response box library reveals the high activity of olorofim against pathogenic Sporothrix species. J Fungi (Basel). https://doi.org/10.3390/jof8101004

    Article  PubMed  PubMed Central  Google Scholar 

  34. Xisto M et al (2023) Promising antifungal molecules against mucormycosis agents identified from pandemic response box (R): in vitro and in silico analyses. J Fungi (Basel). https://doi.org/10.3390/jof9020187

    Article  PubMed  Google Scholar 

  35. de Oliveira HC et al (2022) Screening of the pandemic response box reveals an association between antifungal effects of MMV1593537 and the cell wall of Cryptococcus neoformans, Cryptococcus deuterogattii, and Candida auris. Microbiol Spectr 10(3):e0060122

    Article  PubMed  Google Scholar 

  36. Lim W et al (2022) Screening the pandemic response box identified benzimidazole carbamates, Olorofim and ravuconazole as promising drug candidates for the treatment of eumycetoma. PLoS Negl Trop Dis 16(2):e0010159

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  37. Holwerda M et al (2020) Identification of an antiviral compound from the pandemic response box that efficiently inhibits SARS-CoV-2 infection in vitro. Microorganisms. https://doi.org/10.3390/microorganisms8121872

    Article  PubMed  PubMed Central  Google Scholar 

  38. Shanley, H.T., et al., A High-Throughput Phenotypic Screen of the 'Pandemic Response Box' Identifies a Quinoline Derivative with Significant Anthelmintic Activity. Pharmaceuticals (Basel), 2022. 15(2).

  39. Biendl S, Haberli C, Keiser J (2022) Discovery of novel antischistosomal scaffolds from the open access pandemic response box. Expert Rev Anti Infect Ther 20(4):621–629

    Article  PubMed  CAS  Google Scholar 

  40. Jensen JB, Trager W (1977) Plasmodium falciparum in culture: use of outdated erthrocytes and description of the candle jar method. J Parasitol 63(5):883–886

    Article  PubMed  CAS  Google Scholar 

  41. Johnson JD et al (2007) Assessment and continued validation of the malaria SYBR green I-based fluorescence assay for use in malaria drug screening. Antimicrob Agents Chemother 51(6):1926–1933

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  42. Smilkstein M et al (2004) Simple and inexpensive fluorescence-based technique for high-throughput antimalarial drug screening. Antimicrob Agents Chemother 48(5):1803–1806

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  43. Lambros C, Vanderberg JP (1979) Synchronization of Plasmodium falciparum erythrocytic stages in culture. J Parasitol 65(3):418–420

    Article  PubMed  CAS  Google Scholar 

  44. Mariebernard M, Mohanty A, Rajendran V (2022) A comprehensive review on classifying fast-acting and slow-acting antimalarial agents based on time of action and target organelle of Plasmodium sp. Pathog Dis. https://doi.org/10.1093/femspd/ftac015

    Article  PubMed  Google Scholar 

  45. Sanz LM et al (2012) P falciparum in vitro killing rates allow to discriminate between different antimalarial mode-of-action. PLoS ONE 7(2):e30949

    Article  PubMed  PubMed Central  ADS  CAS  Google Scholar 

  46. Pessanha de Carvalho L, Kreidenweiss A, Held J (2021) Drug repurposing: a review of old and new antibiotics for the treatment of malaria: identifying antibiotics with a fast onset of antiplasmodial action. Molecules. https://doi.org/10.3390/molecules26082304

    Article  PubMed  PubMed Central  Google Scholar 

  47. Nosten F, Brasseur P (2002) Combination therapy for malaria: the way forward? Drugs 62(9):1315–1329

    Article  PubMed  CAS  Google Scholar 

  48. Okada M et al (2020) Doxycycline has distinct apicoplast-specific mechanisms of antimalarial activity. Elife. https://doi.org/10.7554/eLife.60246

    Article  PubMed  PubMed Central  Google Scholar 

  49. Peric M et al (2021) A novel class of fast-acting antimalarial agents: Substituted 15-membered azalides. Br J Pharmacol 178(2):363–377

    Article  PubMed  CAS  Google Scholar 

  50. Pandey AV et al (2001) Mechanism of malarial haem detoxification inhibition by chloroquine. Biochem J 355(Pt 2):333–338

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  51. Shirude PS et al (2012) Quinolinyl pyrimidines: potent inhibitors of NDH-2 as a novel class of anti-TB agents. ACS Med Chem Lett 3(9):736–740

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  52. Dong CK et al (2009) Type II NADH dehydrogenase of the respiratory chain of Plasmodium falciparum and its inhibitors. Bioorg Med Chem Lett 19(3):972–975

    Article  PubMed  CAS  Google Scholar 

  53. Hirschberg J et al (1980) The pleiotropic effects of 33258-Hoechst on the cell cycle in Chinese hamster cells in vitro. Exp Cell Res 130(1):63–72

    Article  PubMed  CAS  Google Scholar 

  54. Marcus M, Sperling K (1979) Condensation–inhibition by 33258-Hoechst of centromeric heterochromatin in prematurely condensed mouse chromosomes. Exp Cell Res 123(2):406–411

    Article  PubMed  CAS  Google Scholar 

  55. Jia X et al (2022) Phosphatase inhibitors BVT-948 and alexidine dihydrochloride inhibit sexual development of the malaria parasite Plasmodium berghei. Int J Parasitol Drugs Drug Resist 19:81–88

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  56. Kumar SP et al (2015) Prioritization of active antimalarials using structural interaction profile of Plasmodium falciparum enoyl-acyl carrier protein reductase (PfENR)-triclosan derivatives. SAR QSAR Environ Res 26(1):61–77

    Article  MathSciNet  PubMed  CAS  Google Scholar 

  57. Dos Reis TF et al (2023) A host defense peptide mimetic, brilacidin, potentiates caspofungin antifungal activity against human pathogenic fungi. Nat Commun 14(1):2052

    Article  PubMed  PubMed Central  ADS  Google Scholar 

  58. Mahajan R (2013) Bedaquiline: First FDA-approved tuberculosis drug in 40 years. Int J Appl Basic Med Res 3(1):1–2

    Article  PubMed  PubMed Central  Google Scholar 

  59. Sahal D et al. (2022) Identification and characterization of GAP50 binders with the goal to identify novel antimalarials. https://doi.org/10.21203/rs.3.rs-1272462/v1

  60. Agrawal, P et al. (2023) Identification of novel, potent, and selective compounds against malaria using Glideosomal Associated Protein 50 as a drug Target. ACS Omega, 8:41 38506–38523

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  61. Holloway GA et al (2007) Discovery of 2-iminobenzimidazoles as a new class of trypanothione reductase inhibitor by high-throughput screening. Bioorg Med Chem Lett 17(5):1422–1427

    Article  PubMed  CAS  Google Scholar 

  62. Sarma GN et al (2003) Glutathione reductase of the malarial parasite Plasmodium falciparum: crystal structure and inhibitor development. J Mol Biol 328(4):893–907

    Article  PubMed  CAS  Google Scholar 

  63. Penna-Coutinho J et al (2011) Antimalarial activity of potential inhibitors of Plasmodium falciparum lactate dehydrogenase enzyme selected by docking studies. PLoS ONE 6(7):e21237

    Article  PubMed  PubMed Central  ADS  CAS  Google Scholar 

  64. Rubin H et al (2015) Acinetobacter baumannii OxPhos inhibitors as selective anti-infective agents. Bioorg Med Chem Lett 25(2):378–383

    Article  PubMed  CAS  Google Scholar 

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Acknowledgements

The V.R. lab is supported by the research grant from Department of Science & Technology (DST), INSPIRE-Faculty Project (DST/INSPIRE/04/2018/003541), Ministry of Science and Technology, Government of India. We thank Pondicherry Institute of Medical Sciences (PIMS) Blood Bank, Puducherry, India, for a continuous blood supply for parasite culture. We gratefully thank the Medicine for Malaria Ventures (MMV, www.mmv.org) for their support and supply of the PRB box.

Funding

This word was funded by Mission on Department of Science & Technology (DST), DST/INSPIRE/04/2018/003541.

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  1. Vinoth Rajendran and Nimitha Cherthedath Naveen have equally contributed to this work.

Authors and Affiliations

  1. Department of Microbiology, School of Life Sciences, Pondicherry University, Puducherry, 605014, India

    Vinoth Rajendran & Nimitha Cherthedath Naveen

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  1. Vinoth Rajendran
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  2. Nimitha Cherthedath Naveen
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VR and NCN: contributed equally toward the literature survey, data interpretation, and preparation of the tables. VR: contributed to the overall supervision, critical analysis of the intellectual content, revision of the manuscript, and funding acquisition. All authors read and approved the final version of the manuscript.

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Correspondence to Vinoth Rajendran.

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Rajendran, V., Naveen, N.C. Identifying Fast and Slow-Acting Antimalarial Compounds of Pandemic Response Box Against Blood-Stage Culture of Plasmodium falciparum 3D7. Curr Microbiol 81, 81 (2024). https://doi.org/10.1007/s00284-023-03601-9

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