The Marine Compound Tartrolon E Targets the Asexual and Early Sexual Stages of

Overview

Journal Microorganisms

Specialty Microbiology

Date 2022 Nov 24

PMID 36422330

Authors

Alexis Cotto-Rosario

Emma Y D Miller

Fernanda G Fumuso

Jason A Clement

Matthew J Todd

Roberta M OConnor

Affiliations

Soon will be listed here.

Abstract

New therapeutic agents for cryptosporidiosis are a critical medical need. The marine organic compound, tartrolon E (trtE), is highly effective against multiple apicomplexan parasites, including . Understanding the mechanism of action of trtE is required to advance in the drug development pipeline. Here, we validate using Nluc parasites for the study of trtE and pinpoint the life stage targeted by trtE. Results show that trtE kills Nluc and wild type with equal efficiency, confirming the use of the Nluc to study this compound. Results revealed that trtE kills the parasite within an hour of treatment and while the compound has no effect on viability of sporozoites, trtE does inhibit establishment of infection. Targeting treatment at particular life cycle stages demonstrated that trtE is effective against asexual of the parasite but has reduced efficacy against mature sexual stages. Gene expression analysis shows that trtE inhibits the early sexual stage of the parasite. Results from these studies will aid the development of trtE as a therapeutic for cryptosporidiosis.

Citing Articles

Norditerpene natural products from subterranean fungi with anti-parasitic activity.

Kolas A, Rusman Y, Maia A, Williams J, Fumuso F, Cotto-Rosario A bioRxiv. 2025; .

PMID: 39803491 PMC: 11722346. DOI: 10.1101/2025.01.02.631097.

References

Boxell A, Hijjawi N, Monis P, Ryan U . Comparison of various staining methods for the detection of Cryptosporidium in cell-free culture. Exp Parasitol. 2008; 120(1):67-72. DOI: 10.1016/j.exppara.2008.04.023. View

Yulfi H, Rozi M, Andriyani Y, Darlan D . Prevalence of Cryptosporidium spp. and Blastocystis hominis in faecal samples among diarrheic HIV patients in Medan, Indonesia. Med Glas (Zenica). 2020; 18(1):55-61. DOI: 10.17392/1271-21. View

Tempone A, Pieper P, Borborema S, Thevenard F, Lago J, Croft S . Marine alkaloids as bioactive agents against protozoal neglected tropical diseases and malaria. Nat Prod Rep. 2021; 38(12):2214-2235. PMC: 8672869. DOI: 10.1039/d0np00078g. View

Manjunatha U, Vinayak S, Zambriski J, Chao A, Sy T, Noble C . A Cryptosporidium PI(4)K inhibitor is a drug candidate for cryptosporidiosis. Nature. 2017; 546(7658):376-380. PMC: 5473467. DOI: 10.1038/nature22337. View

Sparks H, Nair G, Castellanos-Gonzalez A, White Jr A . Treatment of Cryptosporidium: What We Know, Gaps, and the Way Forward. Curr Trop Med Rep. 2015; 2(3):181-187. PMC: 4640180. DOI: 10.1007/s40475-015-0056-9. View

Vanathy K, Parija S, Mandal J, Hamide A, Krishnamurthy S . Cryptosporidiosis: A mini review. Trop Parasitol. 2017; 7(2):72-80. PMC: 5652058. DOI: 10.4103/tp.TP_25_17. View

Vinayak S, Pawlowic M, Sateriale A, Brooks C, Studstill C, Bar-Peled Y . Genetic modification of the diarrhoeal pathogen Cryptosporidium parvum. Nature. 2015; 523(7561):477-80. PMC: 4640681. DOI: 10.1038/nature14651. View

Livak K, Schmittgen T . Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods. 2002; 25(4):402-8. DOI: 10.1006/meth.2001.1262. View

Behera A, Thorpe C, Kidder J, Smith W, Hildebrand E, Hu L . Borrelia burgdorferi-induced expression of matrix metalloproteinases from human chondrocytes requires mitogen-activated protein kinase and Janus kinase/signal transducer and activator of transcription signaling pathways. Infect Immun. 2004; 72(5):2864-71. PMC: 387916. DOI: 10.1128/IAI.72.5.2864-2871.2004. View

10.

Martens M, Liu Y, Sanford A, Wallick A, Warner R, Li R . Analogs of Marinopyrrole A Show Enhancement to Observed Potency against Acute Toxoplasma gondii Infection. Antimicrob Agents Chemother. 2021; 66(1):e0079421. PMC: 8765230. DOI: 10.1128/AAC.00794-21. View

11.

Nachipo P, Hermann D, Quinnan G, Gordon M, Van Voorhis W, Iroh Tam P . Evaluating the safety, tolerability, pharmacokinetics and efficacy of clofazimine in cryptosporidiosis (CRYPTOFAZ): study protocol for a randomized controlled trial. Trials. 2018; 19(1):456. PMC: 6108095. DOI: 10.1186/s13063-018-2846-6. View

12.

Bone Relat R, Winder P, Bowden G, Guzman E, Peterson T, Pomponi S . High-Throughput Screening of a Marine Compound Library Identifies Anti- Activity of Leiodolide A. Mar Drugs. 2022; 20(4). PMC: 9026894. DOI: 10.3390/md20040240. View

13.

Zhang C, Love M, McNamara C, Chi V, Woods A, Joseph S . Pharmacokinetics and Pharmacodynamics of Clofazimine for Treatment of Cryptosporidiosis. Antimicrob Agents Chemother. 2021; 66(1):e0156021. PMC: 8765308. DOI: 10.1128/AAC.01560-21. View

14.

Baragana B, Forte B, Choi R, Hewitt S, Bueren-Calabuig J, Pisco J . Lysyl-tRNA synthetase as a drug target in malaria and cryptosporidiosis. Proc Natl Acad Sci U S A. 2019; 116(14):7015-7020. PMC: 6452685. DOI: 10.1073/pnas.1814685116. View

15.

Sjostrom M, Arvidsson M, Soderstrom L, Lilja M, Lindh J, Widerstrom M . Outbreak of Cryptosporidium hominis in northern Sweden: persisting symptoms in a 5-year follow-up. Parasitol Res. 2022; 121(7):2043-2049. PMC: 9192462. DOI: 10.1007/s00436-022-07524-5. View

16.

Elshahawi S, Trindade-Silva A, Hanora A, Han A, Flores M, Vizzoni V . Boronated tartrolon antibiotic produced by symbiotic cellulose-degrading bacteria in shipworm gills. Proc Natl Acad Sci U S A. 2013; 110(4):E295-304. PMC: 3557025. DOI: 10.1073/pnas.1213892110. View

17.

Omolabi K, Odeniran P, Soliman M . A meta-analysis of species in humans from southern Africa (2000-2020). J Parasit Dis. 2021; 46(1):304-316. PMC: 8371598. DOI: 10.1007/s12639-021-01436-4. View

18.

Kato S, Lindergard G, Mohammed H . Utility of the Cryptosporidium oocyst wall protein (COWP) gene in a nested PCR approach for detection infection in cattle. Vet Parasitol. 2003; 111(2-3):153-9. DOI: 10.1016/s0304-4017(02)00353-9. View

19.

Godiwala N, Vandewalle A, Ward H, Leav B . Quantification of in vitro and in vivo Cryptosporidium parvum infection by using real-time PCR. Appl Environ Microbiol. 2006; 72(6):4484-8. PMC: 1489663. DOI: 10.1128/AEM.00189-06. View

20.

Love M, McNamara C . Phenotypic screening techniques for drug discovery. Expert Opin Drug Discov. 2020; 16(1):59-74. DOI: 10.1080/17460441.2020.1812577. View