A Novel Fungal Metabolite Inhibits Plasmodium Falciparum Transmission and Infection

Overview

Journal Parasit Vectors

Publisher Biomed Central

Specialties Parasitology
Tropical Medicine

Date 2021 Mar 25

PMID 33761961

Citations 7

Authors

Guodong Niu

Xiaohong Wang

Yue Hao

Shambhu Kandel

Guomin Niu

Raphael G Raptis

Jun Li

Affiliations

Soon will be listed here.

Abstract

Background: Malaria transmission depends on infected mosquitoes and can be controlled by transmission-blocking drugs. The recently discovered FREP1-mediated malaria transmission pathway is an excellent target to screen drugs for limiting transmission.

Methods: To identify candidate small molecules, we used an ELISA-based approach to analyze extracts from a fungal library for inhibition of the FREP1-parasite interaction. We isolated and determined one active compound by chromatography and crystallography, respectively. We measured the effects of the bioactive compound on malaria transmission to mosquitoes through standard membrane-feeding assays (SMFA) and on parasite proliferation in blood by culturing.

Results: We discovered the ethyl acetate extract of the fungus Purpureocillium lilacinum that inhibited Plasmodium falciparum transmission to mosquitoes. Pre-exposure to the extract rendered Anopheles gambiae resistant to Plasmodium infection. Furthermore, we isolated one novel active compound from the extract and identified it as 3-amino-7,9-dihydroxy-1-methyl-6H-benzo[c]chromen-6-one, or "pulixin." Pulixin prevented FREP1 from binding to P. falciparum-infected cell lysate. Pulixin blocked the transmission of the parasite to mosquitoes with an EC (the concentration that gave half-maximal response) of 11 µM based on SMFA. Notably, pulixin also inhibited the proliferation of asexual-stage P. falciparum with an EC of 47 nM. The compound did not show cytotoxic effects at a concentration of 116 µM or lower.

Conclusion: By targeting the FREP1-Plasmodium interaction, we discovered that Purpureocillium lilacinum extract blocked malaria transmission. We isolated and identified the bioactive agent pulixin as a new compound capable of stopping malaria transmission to mosquitoes and inhibiting parasite proliferation in blood culture.

Citing Articles

Leucinostatins target Plasmodium mitochondria to block malaria transmission.

Niu G, Wang X, Li J Parasit Vectors. 2024; 17(1):524.

PMID: 39707527 PMC: 11660961. DOI: 10.1186/s13071-024-06608-8.

Leucinostatins from fungal extracts block malaria transmission to mosquitoes.

Niu G, Wang X, Gao W, Cui L, Li J Parasit Vectors. 2024; 17(1):401.

PMID: 39304934 PMC: 11414030. DOI: 10.1186/s13071-024-06450-y.

Arsinothricin Inhibits Proliferation in Blood and Blocks Parasite Transmission to Mosquitoes.

Yoshinaga M, Niu G, Yoshinaga-Sakurai K, Nadar V, Wang X, Rosen B Microorganisms. 2023; 11(5).

PMID: 37317169 PMC: 10222646. DOI: 10.3390/microorganisms11051195.

Contemporary exploitation of natural products for arthropod-borne pathogen transmission-blocking interventions.

Muema J, Bargul J, Obonyo M, Njeru S, Matoke-Muhia D, Mutunga J Parasit Vectors. 2022; 15(1):298.

PMID: 36002857 PMC: 9404607. DOI: 10.1186/s13071-022-05367-8.

Crystal Structure Determination and Hirshfeld Analysis of a New Alternariol Packing Polymorph.

Rue K, Niu G, Li J, Raptis R Crystals (Basel). 2022; 12(5).

PMID: 35968538 PMC: 9374539. DOI: 10.3390/cryst12050579.

References

Wu T, Nagle A, Kuhen K, Gagaring K, Borboa R, Francek C . Imidazolopiperazines: hit to lead optimization of new antimalarial agents. J Med Chem. 2011; 54(14):5116-30. PMC: 6950218. DOI: 10.1021/jm2003359. View

Meister S, Plouffe D, Kuhen K, Bonamy G, Wu T, Barnes S . Imaging of Plasmodium liver stages to drive next-generation antimalarial drug discovery. Science. 2011; 334(6061):1372-7. PMC: 3473092. DOI: 10.1126/science.1211936. View

Leong F, Zhao R, Zeng S, Magnusson B, Diagana T, Pertel P . A first-in-human randomized, double-blind, placebo-controlled, single- and multiple-ascending oral dose study of novel Imidazolopiperazine KAF156 to assess its safety, tolerability, and pharmacokinetics in healthy adult volunteers. Antimicrob Agents Chemother. 2014; 58(11):6437-43. PMC: 4249437. DOI: 10.1128/AAC.03478-14. View

Liu N . Insecticide resistance in mosquitoes: impact, mechanisms, and research directions. Annu Rev Entomol. 2015; 60:537-59. DOI: 10.1146/annurev-ento-010814-020828. View

Namountougou M, Simard F, Baldet T, Diabate A, Ouedraogo J, Martin T . Multiple insecticide resistance in Anopheles gambiae s.l. populations from Burkina Faso, West Africa. PLoS One. 2012; 7(11):e48412. PMC: 3506617. DOI: 10.1371/journal.pone.0048412. View

Antonio-Nkondjio C, Defo-Talom B, Tagne-Fotso R, Tene-Fossog B, Ndo C, Lehman L . High mosquito burden and malaria transmission in a district of the city of Douala, Cameroon. BMC Infect Dis. 2012; 12:275. PMC: 3532071. DOI: 10.1186/1471-2334-12-275. View

Povelones M, Waterhouse R, Kafatos F, Christophides G . Leucine-rich repeat protein complex activates mosquito complement in defense against Plasmodium parasites. Science. 2009; 324(5924):258-61. PMC: 2790318. DOI: 10.1126/science.1171400. View

Riehle M, Markianos K, Niare O, Xu J, Li J, Toure A . Natural malaria infection in Anopheles gambiae is regulated by a single genomic control region. Science. 2006; 312(5773):577-9. DOI: 10.1126/science.1124153. View

Zhang G, Niu G, Franca C, Dong Y, Wang X, Butler N . Anopheles Midgut FREP1 Mediates Plasmodium Invasion. J Biol Chem. 2015; 290(27):16490-501. PMC: 4505404. DOI: 10.1074/jbc.M114.623165. View

10.

Niu G, Franc A C, Zhang G, Roobsoong W, Nguitragool W, Wang X . The fibrinogen-like domain of FREP1 protein is a broad-spectrum malaria transmission-blocking vaccine antigen. J Biol Chem. 2017; 292(28):11960-11969. PMC: 5512087. DOI: 10.1074/jbc.M116.773564. View

11.

Mosesson M . Fibrinogen and fibrin structure and functions. J Thromb Haemost. 2005; 3(8):1894-904. DOI: 10.1111/j.1538-7836.2005.01365.x. View

12.

Doolittle R, McNamara K, Lin K . Correlating structure and function during the evolution of fibrinogen-related domains. Protein Sci. 2012; 21(12):1808-23. PMC: 3575912. DOI: 10.1002/pro.2177. View

13.

Han J, Zhang S, Niu J, Zhang C, Dai W, Wu Y . Development of Taccalonolide AJ-Hydroxypropyl-β-Cyclodextrin Inclusion Complexes for Treatment of Clear Cell Renal-Cell Carcinoma. Molecules. 2020; 25(23). PMC: 7731059. DOI: 10.3390/molecules25235586. View

14.

Niu G, Wang B, Zhang G, King J, Cichewicz R, Li J . Targeting mosquito FREP1 with a fungal metabolite blocks malaria transmission. Sci Rep. 2015; 5:14694. PMC: 4593950. DOI: 10.1038/srep14694. View

15.

Paton D, Childs L, Itoe M, Holmdahl I, Buckee C, Catteruccia F . Exposing Anopheles mosquitoes to antimalarials blocks Plasmodium parasite transmission. Nature. 2019; 567(7747):239-243. PMC: 6438179. DOI: 10.1038/s41586-019-0973-1. View

16.

Niu G, Annamalai T, Wang X, Li S, Munga S, Niu G . A diverse global fungal library for drug discovery. PeerJ. 2020; 8:e10392. PMC: 7703384. DOI: 10.7717/peerj.10392. View

17.

Katoh K, Standley D . A simple method to control over-alignment in the MAFFT multiple sequence alignment program. Bioinformatics. 2016; 32(13):1933-42. PMC: 4920119. DOI: 10.1093/bioinformatics/btw108. View

18.

Cui Y, Niu G, Li V, Wang X, Li J . Analysis of blood-induced Anopheles gambiae midgut proteins and sexual stage Plasmodium falciparum interaction reveals mosquito genes important for malaria transmission. Sci Rep. 2020; 10(1):14316. PMC: 7459308. DOI: 10.1038/s41598-020-71186-5. View

19.

Luangsa-Ard J, Houbraken J, van Doorn T, Hong S, Borman A, Hywel-Jones N . Purpureocillium, a new genus for the medically important Paecilomyces lilacinus. FEMS Microbiol Lett. 2011; 321(2):141-9. DOI: 10.1111/j.1574-6968.2011.02322.x. View

20.

Omar R, Li L, Yuan T, Seeram N . α-Glucosidase inhibitory hydrolyzable tannins from Eugenia jambolana seeds. J Nat Prod. 2012; 75(8):1505-9. DOI: 10.1021/np300417q. View