Activities of anti-Toxoplasma drugs and compounds against tissue cysts in the last three decades (1987 to 2017), a systematic review
- 401 Downloads
Currently, there is no approved therapy that can eradicate Toxoplasma gondii tissue cysts, which are responsible for chronic infection. This systematic review was performed to assess drugs or compounds that can be used as anti-T. gondii tissue cysts in vitro and in vivo. English electronic databases (i.e., PubMed, Science Direct, Scopus, Google Scholar, and Web of Science) were systematically searched for articles published up to 2017. A total of 55 papers published from 1987 to 2017 were eligible for inclusion in this systematic review. Among the drugs, atovaquone and azithromycin were found effective after long-term inoculation into mice; however, clinical cases of resistance to these drugs have been reported. Also, FR235222, QUI-11, tanshinone IIA, and hydroxyzine were shown to be effective against Toxoplasma cysts, but their effectiveness in vivo remains unknown. Additionally, compound 32, endochin-like quinolones, miltefosine, and guanabenz can be used as effective antiparasitic with the unique ability to reduce brain tissue cysts in chronically infected mice. Importantly, these antimicrobial agents are significant criteria for drug candidates. Future studies should focus on the biology and drug susceptibility of the cyst form of T. gondii in chronic toxoplasmosis patients to find more effective strategies that have sterilizing activity for eliminating T. gondii tissue cysts from the host, preventing disease relapse and potentially shortening the required duration of drug administration.
KeywordsToxoplasma gondii Toxoplasmosis Drugs Compounds Tissue cysts
We would like to thank the Vice Chancellors for Research of the Mazandaran University of Medical Sciences, Sari, Iran (grant number 1430) for the financial support. We would also like to thank the Student Research Committee, Mazandaran University of Medical Sciences, Sari, Iran.
A.D. and M.S. designed the systematic review protocol; M.M., S.S.H., and S.H.S. searched the databases for potentially eligible articles based on their titles and abstracts; M.M. and S.S.H. extracted the data; M.M. wrote the manuscript; and S.M. critically reviewed the manuscript. All the authors read and approved the final manuscript for publication.
Compliance with ethical standards
The authors declare that there is no conflict of interest.
- Afifi MA, Jiman-Fatani AA, Al-Rabia MW, Al-Hussainy NH (2014) Application of a phosphodiesterase-4 (PDE4) inhibitor to abort chronic toxoplasmosis and to mitigate consequential pathological changes. JMAU 2(2):94–99Google Scholar
- Alqaisi A, Mbekeani A, Llorens MB, Elhammer A, Denny P (2017) The antifungal Aureobasidin A and an analogue are active against the protozoan parasite Toxoplasma gondii but do not inhibit sphingolipid biosynthesis. Parasitology 1–8Google Scholar
- Bottari NB, Baldissera MD, Tonin AA, Rech VC, Alves CB, D'Avila F, Thomé GR, Guarda NS, Moresco RN, Camillo G, Vogel FF, Luchese C, Schetinger MRC, Morsch VM, Tochetto C, Fighera R, Nishihira VSK, da Silva AS (2016) Synergistic effects of resveratrol (free and inclusion complex) and sulfamethoxazole-trimetropim treatment on pathology, oxidant/antioxidant status and behavior of mice infected with Toxoplasma gondii. Microb Pathog 95:166–174CrossRefPubMedGoogle Scholar
- Braga-Silva CF, Suhett CSR, Drozino RN, Moreira NM, Sant’Ana DMG, de Araújo SM (2016) Biotherapic of Toxoplasma gondii reduces parasite load, improves experimental infection, protects myenteric neurons and modulates the immune response in mice with toxoplasmosis. Eur J Integr Med 8(5):865–874CrossRefGoogle Scholar
- Chew WK, Segarra I, Ambu S, Mak JW (2012) Significant reduction of brain cysts caused by Toxoplasma gondii after treatment with spiramycin coadministered with metronidazole in a mouse model of chronic toxoplasmosis. Antimicrob Agents Chemother 56(4):1762–1768CrossRefPubMedCentralPubMedGoogle Scholar
- Chirgwin K, Hafner R, Leport C, Remington J, Andersen J, Bosler EM, Roque C, Rajicic N, McAuliffe V, Morlat P, Jayaweera DT, Vilde JL, Luft BJ, the AIDS Clinical Trials Group 237/Agence Nationale de Recherche sur le SIDA, Essai 039 Study Team (2002) Randomized phase II trial of atovaquone with pyrimethamine or sulfadiazine for treatment of toxoplasmic encephalitis in patients with acquired immunodeficiency syndrome: ACTG 237/ANRS 039 study. Clin Infect Dis 34(9):1243–1250CrossRefPubMedGoogle Scholar
- Doggett JS, Nilsen A, Forquer I, Wegmann KW, Jones-Brando L, Yolken RH, Bordon C, Charman SA, Katneni K, Schultz T, Burrows JN, Hinrichs DJ, Meunier B, Carruthers VB, Riscoe MK (2012) Endochin-like quinolones are highly efficacious against acute and latent experimental toxoplasmosis. Proc Natl Acad Sci 109(39):15936–15941CrossRefPubMedGoogle Scholar
- Doleski PH, Leal DBR, Machado VS, Bottari NB, Manzoni AG, Casali EA, Moritz CEJ, Rocha ACA, Camillo G, Vogel FF, Stefani LM, Mendes RE, da Silva AS (2017a) Diphenyl diselenide modulates nucleotidases, reducing inflammatory responses in the liver of Toxoplasma gondii-infected mice. Purinergic Signal 13(4):489–496CrossRefPubMedCentralPubMedGoogle Scholar
- Doleski PH, ten Caten MV, Passos DF, Castilhos LG, Leal DBR, Machado VS, Bottari NB, Vogel FF, Mendes RE, da Silva AS (2017b) Toxoplasmosis treatment with diphenyl diselenide in infected mice modulates the activity of purinergic enzymes and reduces inflammation in spleen. Exp Parasitol 181:7–13CrossRefPubMedGoogle Scholar
- Dubey J (1977) Toxoplasma, Hammondia, Besnoitia, Sarcocystis, and other tissue cyst-forming coccidia of man and animals. Parasitic Protozoa 3:101–237Google Scholar
- Ferguson D, Huskinson-Mark J, Araujo F, Remington J (1994) An ultrastructural study of the effect of treatment with atovaquone in brains of mice chronically infected with the ME49 strain of Toxoplasma gondii. Int J Clin Exp Pathol 75(2):111Google Scholar
- Kul O, Yildiz K, Ocal N, Freyre A, Deniz A, Karahan S, Atmaca HT, Gokpinar S, Dincel GC, Uzunalioğlu T, Terzi OS (2013) In-vivo efficacy of toltrazuril on experimentally induced Toxoplasma gondii tissue cysts in lambs: a novel strategy for prevention of human exposure to meat-borne toxoplasmosis. Res Vet Sci 94(2):269–276CrossRefPubMedGoogle Scholar
- Machado VS, Bottari NB, Baldissera MD, Isabel de Azevedo M, Rech VC, Ianiski FR, Vaucher RA, Mendes RE, Camillo G, Vogel FF, de la Rue ML, Carmo GM, Tonin AA, da Silva AS (2016) Toxoplasma gondii: effects of diphenyl diselenide in experimental toxoplasmosis on biomarkers of cardiac function. Exp Parasitol 167:25–31CrossRefPubMedGoogle Scholar
- Mahmoud DM, Mahmoud MS, Ezz-El-Din HM, Abo-Zahra FA, Meselhey RA (2017) Artesunate effect on RH virulent and ME49 non-virulent strains of Toxoplasma gondii: in vitro and in vivo experimental studies. Sci Parasitol 17:83–92Google Scholar
- Maubon D, Bougdour A, Wong YS, Brenier-Pinchart MP, Curt A, Hakimi MA, Pelloux H (2010) Activity of the histone deacetylase inhibitor FR235222 on Toxoplasma gondii: inhibition of stage conversion of the parasite cyst form and study of new derivative compounds. Antimicrob Agents Chemother 54(11):4843–4850CrossRefPubMedCentralPubMedGoogle Scholar
- Mokua Mose J et al (2017) Development of neurological mouse model for toxoplasmosis using Toxoplasma gondii isolated from chicken in Kenya Patholog Res Int 2017Google Scholar
- Rutaganira FU, Barks J, Dhason MS, Wang Q, Lopez MS, Long S, Radke JB, Jones NG, Maddirala AR, Janetka JW, el Bakkouri M, Hui R, Shokat KM, Sibley LD (2017) Inhibition of calcium dependent protein kinase 1 (CDPK1) by pyrazolopyrimidine analogs decreases establishment and reoccurrence of central nervous system disease by Toxoplasma gondii. J Med Chem 60(24):9976–9989CrossRefPubMedGoogle Scholar
- Scallan E et al (2011) Foodborne illness acquired in the United States—major pathogens. Emerg Infect Dis 17(1)Google Scholar
- Shu H, Jiang L (2002) Effect of garlicin and minocycline on the cyst formation of Toxoplasma gondii in mice. Chinese Journal of Zoonoses 18(1):100–101Google Scholar
- Vidadala RSR, Rivas KL, Ojo KK, Hulverson MA, Zambriski JA, Bruzual I, Schultz TL, Huang W, Zhang Z, Scheele S, DeRocher AE, Choi R, Barrett LK, Siddaramaiah LK, Hol WGJ, Fan E, Merritt EA, Parsons M, Freiberg G, Marsh K, Kempf DJ, Carruthers VB, Isoherranen N, Doggett JS, van Voorhis WC, Maly DJ (2016) Development of an orally available and central nervous system (CNS) penetrant Toxoplasma gondii calcium-dependent protein kinase 1 (Tg CDPK1) inhibitor with minimal human ether-a-go-go-related gene (hERG) activity for the treatment of toxoplasmosis. J Med Chem 59(13):6531–6546CrossRefPubMedCentralPubMedGoogle Scholar