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Mini-Reviews in Medicinal Chemistry


ISSN (Print): 1389-5575
ISSN (Online): 1875-5607

Review Article

Brain-eating Amoebae Infection: Challenges and Opportunities in Chemotherapy

Author(s): Mohammad Ridwane Mungroo, Ayaz Anwar, Naveed Ahmed Khan* and Ruqaiyyah Siddiqui

Volume 19, Issue 12, 2019

Page: [980 - 987] Pages: 8

DOI: 10.2174/1389557519666190313161854

Price: $65


Pathogenic free-living amoeba are known to cause a devastating infection of the central nervous system and are often referred to as “brain-eating amoebae”. The mortality rate of more than 90% and free-living nature of these amoebae is a cause for concern. It is distressing that the mortality rate has remained the same over the past few decades, highlighting the lack of interest by the pharmaceutical industry. With the threat of global warming and increased outdoor activities of public, there is a need for renewed interest in identifying potential anti-amoebic compounds for successful prognosis. Here, we discuss the available chemotherapeutic options and opportunities for potential strategies in the treatment and diagnosis of these life-threatening infections.

Keywords: Brain-eating amoebae, Acanthamoeba, Naegleria, Balamuthia, survival, in vitro, drugs.

Graphical Abstract
Martinez, A.J. Free-living amoebas: Natural history, prevention, diagnosis, pathology and treatment of disease, 1st ed; CRC Press, 1985.
Martinez, A.J.; Visvesvara, G.S. Free-living, amphizoic and opportunistic amebas. Brain Pathol., 1997, 583-598.
Schuster, F.L.; Visvesvara, G.S. Opportunistic amoebae: Challenges in prophylaxis and treatment; Drug Resist, 2004, pp. 41-51.
Visvesvara, G.S. Infections with free-living amebae. Handb. Clin. Neurol., 2013, 14, 153-168.
Larkin, D.F.; Kilvington, S.; Dart, J.K. Treatment of Acanthamoeba keratitis with polyhexamethylene biguanide. Ophthalmology, 1992, 99, 185-191.
[ 3.]
Burger, R.M.; Franco, R.J.; Drlica, K. Killing acanthamoebae with polyaminopropyl biguanide: Quantitation and kinetics. Antimicrob. Agents Chemother., 1994, 38, 886-888.
[ 38.4.886.]
Aichelburg, A.C.; Walochnik, J.; Assadian, O.; Prosch, H.; Steuer, A.; Perneczky, G.; Visvesvara, G.S.; Aspöck, H.; Vetter, N. Successful treatment of disseminated Acanthamoeba sp. infection with miltefosine. Emerg. Infect. Dis., 2008, 14, 1743-1746.
[ eid1411.070854]
Nagington, J.; Richards, J.E. Chemotherapeutic compounds and Acanthamoebae from eye infections. J. Clin. Pathol., 1976, 29, 648-651.
Sison, J.P.; Kemper, C.A.; Loveless, M.; McShane, D.; Visvesvara, G.S.; Deresinski, S.C. Disseminated acanthamoeba infection in patients with AIDS: Case reports and review. Clin. Infect. Dis., 1995, 20, 1207-1216.
Seijo Martinez, M.; Gonzalez-Mediero, G.; Santiago, P.; Rodriguez De Lope, A.; Diz, J.; Conde, C.; Visvesvara, G.S. Granulomatous amebic encephalitis in a patient with AIDS: Isolation of acanthamoeba sp. Group II from brain tissue and successful treatment with sulfadiazine and fluconazole. J. Clin. Microbiol., 2000, 38, 3892-3895.
Singhal, T.; Bajpai, A.; Kalra, V.; Kabra, S.K.; Samantaray, J.C.; Satpathy, G.; Gupta, A.K. Successful treatment of acanthamoeba meningitis with combination oral antimicrobials. Pediatr. Infect. Dis. J., 2001, 20, 623-627.
Walia, R.; Montoya, J.G.; Visvesvera, G.S.; Booton, G.C.; Doyle, R.L. A case of successful treatment of cutaneous acanthamoeba infection in a lung transplant recipient. Transpl. Infect. Dis., 2007, 9, 51-54.
Maritschnegg, P.; Sovinz, P.; Lackner, H.; Benesch, M.; Nebl, A.; Schwinger, W.; Walochnik, J.; Urban, C. Granulomatous amebic encephalitis in a child with acute lymphoblastic leukemia successfully treated with multimodal antimicrobial therapy and hyperbaric oxygen. J. Clin. Microbiol., 2011, 49, 446-448.
[ JCM.01456-10]
Umar, I.; Kolyvas, G.; Visvesvara, G.S.; Bilbao, J.; Guiot, M-C.; Duplisea, K.; Qvarnstrom, Y.; Webster, D. Treatment of granulomatous amoebic encephalitis with voriconazole and miltefosine in an immunocompetent soldier. Am. J. Trop. Med. Hyg., 2012, 87, 715-718.
Seidel, J.S.; Harmatz, P.; Visvesvara, G.S.; Cohen, A.; Edwards, J.; Turner, J. Successful treatment of primary amebic meningoencephalitis. N. Engl. J. Med., 1982, 306, 346-348.
[ NEJM198202113060607]
Brown, R.L. Successful treatment of primary amebic meningoencephalitis. Arch. Intern. Med., 1991, 151, 1201.
[ archinte.1991.00400060121021]
Wang, A.; Kay, R.; Poon, W.S.; Ng, H.K. Successful treatment of amoebic meningoencephalitis in a chinese living in hong kong. Clin. Neurol. Neurosurg., 1993, 95, 249-252.
Jain, R.; Prabhakar, S.; Modi, M.; Bhatia, R.; Sehgal, R. Naegleria meningitis: A rare survival. Neurol. India, 2002, 50, 470-472. (accessed November 28, 2018)
Vargas-Zepeda, J.; Gómez-Alcalá, A.V.; Vázquez-Morales, J.A.; Licea-Amaya, L.; De Jonckheere, J.F.; Lares-Villa, F. Successful treatment of naegleria fowleri meningoencephalitis by using intravenous amphotericin b, fluconazole and rifampicin. Arch. Med. Res., 2005, 36, 83-86.
Linam, W.M.; Ahmed, M.; Cope, J.R.; Chu, C.; Visvesvara, G.S.; da Silva, A.J.; Qvarnstrom, Y.; Green, J. Successful treatment of an adolescent with Naegleria fowleri primary amebic meningoencephalitis. Pediatrics, 2015, 135, e744-e748.
[ peds.2014-2292]
Deetz, T.R.; Sawyer, M.H.; Billman, G.; Schuster, F.L.; Visvesvara, G.S. Successful treatment of Balamuthia amoebic encephalitis: Presentation of 2 Cases. Clin. Infect. Dis., 2003, 37, 1304-1312.
Jung, S.; Schelper, R.L.; Visvesvara, G.S.; Chang, H.T. Balamuthia mandrillaris meningoencephalitis in an immunocompetent patient: An unusual clinical course and a favorable outcome. Arch. Pathol. Lab. Med., 2004, 128, 466-468.
Martínez, D.Y.; Seas, C.; Bravo, F.; Legua, P.; Ramos, C.; Cabello, A.M.; Gotuzzo, E. Successful treatment of balamuthia mandrillaris amoebic infection with extensive neurological and cutaneous involvement. Clin. Infect. Dis., 2010, 51, e7-e11.
[ 653609]
Cary, L.C.; Maul, E.; Potter, C.; Wong, P.; Nelson, P.T.; Given, C.; Robertson, W. Balamuthia mandrillaris meningoencephalitis: Survival of a pediatric patient. Pediatrics, 2010, 125, e699-e703.
Anwar, A.; Siddiqui, R.; Shah, M.R.; Khan, N.A. Gold nanoparticle-conjugated cinnamic acid exhibits antiacanthamoebic and antibacterial properties. Antimicrob. Agents Chemother., 2018, 62, e00630-e18.
Arshia, F.; Ahad, N.; Ghouri, K.; Khan, K.M.; Perveen, S.; Choudhary, M.I. Synthesis of 4-substituted ethers of benzophenone and their anti-leishmanial activities. R. Soc. Open Sci., 2018, 5171771
Rathelot, P.; Azas, N.; El-Kashef, H.; Delmas, F.; Di Giorgio, C.; Timon-David, P.; Maldonado, J.; Vanelle, P. 1, 3-diphenylpyrazoles: Synthesis and antiparasitic activities of azomethine derivatives. Eur. J. Med. Chem., 2002, 37, 671-679.
Mahboob, T.; Azlan, A.M.; Shipton, F.N.; Boonroumkaew, P.; Azman, N.S.; Sekaran, S.D.; Ithoi, I.; Tan, T.C.; Samudi, C.; Wiart, C.; Nissapatorn, V. Acanthamoebicidal activity of periglaucine A and betulinic acid from Pericampylus glaucus (Lam.) Merr. in vitro. Exp. Parasitol., 2017, 183, 160-166.
Aqeel, Y.; Iqbal, J.; Siddiqui, R.; Gilani, A.H.; Khan, N.A. Anti-acanthamoebic properties of resveratrol and demethoxycurcumin. Exp. Parasitol., 2012, 132(4), 519-523.
McClellan, K.; Howard, K.; Niederkorn, J.Y.; Alizadeh, H. Effect of steroids on Acanthamoeba cysts and trophozoites. Invest. Ophthalmol. Vis. Sci., 2001, 42(12), 2885-2893.
Kilvington, S.; Larkin, D.F.; White, D.G.; Beeching, J.R. Laboratory investigation of Acanthamoeba keratitis. J. Clin. Microbiol., 1990, 28, 2722-2725.
Bouyer, S.; Imbert, C.; Daniault, G.; Cateau, E.; Rodier, M-H. Effect of caspofungin on trophozoites and cysts of three species of Acanthamoeba. J. Antimicrob. Chemother., 2006, 59, 122-124.
Raederstorff, D.; Rohmer, M. Sterol biosynthesis de nova via cycloartenol by the soil amoeba Acanthamoeba polyphaga. Biochem. J., 1985, 231, 609-615.
Duma, R.J.; Finley, R. In vitro susceptibility of pathogenic Naegleria and Acanthamoeba speicies to a variety of therapeutic agents. Antimicrob. Agents Chemother., 1976, 10, 370-376.
[ AAC.10.2.370]
Cabello-Vílchez, A.M.; Martín-Navarro, C.M.; López-Arencibia, A.; Reyes-Batlle, M.; Sifaoui, I.; Valladares, B.; Piñero, J.E.; Lorenzo-Morales, J. Voriconazole as a first-line treatment against potentially pathogenic Acanthamoeba strains from Peru. Parasitol. Res., 2014, 113, 755-759.
Ondarza, R.N.; Iturbe, A.; Hernández, E. In vitro antiproliferative effects of neuroleptics, antimycotics and antibiotics on the human pathogens Acanthamoeba polyphaga and Naegleria fowleri. Arch. Med. Res., 2006, 37, 723-729.
Polat, Z.A.; Savage, P.B.; Genberg, C. In vitro amoebicidal activity of a ceragenin, cationic steroid antibiotic-13, against Acanthamoeba castellanii and its cytotoxic potential. J. Ocul. Pharmacol. Ther., 2011, 27, 1-5.
Matoba, A.Y.; Pare, P.D.; Le, T.D.; Osato, M.S. The effects of freezing and antibiotics on the viability of Acanthamoeba Cysts., Arch. Ophthalmol., 1989, 107-439.
[ 10449043]
Khan, N.A. Acanthamoeba: Biology and pathogenesis; Caister Academic Press, 2015.
Mehlotra, R.K.; Shukla, O.P. In vitro susceptibility of Acanthamoeba culbertsoni to inhibitors of folate biosynthesis. J. Eukaryot. Microbiol., 1993, 40, 14-17.
Stevens, A.R.; O’Dell, W.D. In vitro and in vivo activity of 5-fluorocytosine on Acanthamoeba. Antimicrob. Agents Chemother., 1974, 6, 282-289.
Orfeo, T.; Chen, L.; Huang, W.; Ward, G.; Bateman, E. Distamycin A selectively inhibits Acanthamoeba RNA synthesis and differentiation. Biochim. Biophys. Acta Gene Struct. Expr., 1999, 1446, 273-285.
Debnath, A.; Tunac, J.B.; Silva-Olivares, A.; Galindo-Gómez, S. Shibayama, M.; McKerrow, J.H. In vitro efficacy of corifungin against Acanthamoeba castellanii trophozoites and cysts. Antimicrob. Agents Chemother., 2014, 58, 1523-1528.
[ AAC.02254-13]
Mattana, A.; Biancu, G.; Alberti, L.; Accardo, A.; Delogu, G. Fiori; Cappuccinelli, P. In vitro evaluation of the effectiveness of the macrolide rokitamycin and chlorpromazine against Acanthamoeba castellanii. Antimicrob. Agents Chemother., 2004, 48, 4520-4527.
Fürnkranz, U.; Nagl, M.; Gottardi, W.; Köhsler, M.; Aspöck, H.; Walochnik, J. Cytotoxic activity of N-chlorotaurine on Acanthamoeba spp. Antimicrob. Agents Chemother., 2008, 470-476.
Nacapunchai, D.; Phadungkul, K.; Kaewcharus, S. In vitro effect of artesunate against Acanthamoeba spp, 2002. (accessed November 28, 2018).
Perrine, D.; Chenu, J.P.; Georges, P.; Lancelot, J.C.; Saturnino, C.; Robba, M. Amoebicidal efficiencies of various diamidines against two strains of Acanthamoeba polyphaga. Antimicrob. Agents Chemother., 1995, 39, 339-342.
Lim, N.; Goh, D.; Bunce, C.; Xing, W.; Fraenkel, G.; Poole, T.R.G.; Ficker, L. Comparison of polyhexamethylene biguanide and chlorhexidine as monotherapy agents in the treatment of Acanthamoeba keratitis. Am. J. Ophthalmol., 2008, 145, 130-135.
Alizadeh, H.; Neelam, S.; Cavanagh, H.D. Amoebicidal activities of alexidine against 3 pathogenic strains of Acanthamoeba. Eye Contact Lens, 2009, 35, 1-5.
Mrva, M.; Garajová, M.; Lukáč, M.; Ondriska, F. Weak cytotoxic activity of miltefosine against clinical isolates of Acanthamoeba spp. J. Parasitol., 2011, 97, 538-540.
Walochnik, J.; Duchêne, M.; Seifert, K.; Obwaller, A.; Hottkowitz, T.; Wiedermann, G.; Eibl, H.; Aspöck, H. Cytotoxic activities of alkylphosphocholines against clinical isolates of Acanthamoeba spp. Antimicrob. Agents Chemother., 2002, 46, 695-701.
Polat, Z.A.; Obwaller, A.; Vural, A.; Walochnik, J. Efficacy of miltefosine for topical treatment of Acanthamoeba keratitis in Syrian hamsters. Parasitol. Res., 2012, 110, 515-520.
[ s00436-011-2515-0]
Obwaller, A.; Polat, Z.; Walochnik, J.; Vural, A.; Dursum, A.; Arici, M. Arici, M. Miltefosine and polyhexamethylene biguanide, a new drug combination for the treatment of Acanthamoeba keratitis. Results from in-vivo toxicological and efficacy studies. Acta Ophthalmol., 2012, 90, 0-0.
Capewell, L.G.; Harris, A.M.; Yoder, J.S.; Cope, J.R.; Eddy, B.A.; Roy, S.L.; Visvesvara, G.S.; Fox, L.M.; Beach, M.J. Diagnosis, clinical course, and treatment of primary amoebic meningoencephalitis in the United States, 1937-2013. J. Pediatric Infect. Dis. Soc., 2015, 4, e68-e75.
Stone, N.R.H.; Bicanic, T.; Salim, R.; Hope, W. Liposomal amphotericin B (AmBisome®): A review of the pharmacokinetics, pharmacodynamics, clinical experience and future directions. Drugs, 2016, 76, 485-500.
Thong, Y.H.; Rowan-Kelly, B.; Ferrante, A. Treatment of experimental Naegleria meningoencephalitis with a combination of amphotericin B and rifamycin. Scand. J. Infect. Dis., 1979, 11, 151-153.
Wehrli, W. Rifampin: Mechanisms of action and resistance. Clin. Infect. Dis 1983, 5, S407-S411.
[ Supplement_ 3.S407.]
Cope, J.R.; Ratard, R.C.; Hill, V.R.; Sokol, T.; Causey, J.J.; Yoder, J.S.; Mirani, G.; Mull, B.; Mukerjee, K.A.; Narayanan, J.; Doucet, M.; Qvarnstrom, Y.; Poole, C.N.; Akingbola, O.A.; Ritter, J.M.; Xiong, Z.; da Silva, A.J.; Roellig, D.; Van Dyke, R.B.; Stern, H.; Xiao, L.; Beach, M.J. The first association of a primary amebic meningoencephalitis death with culturable Naegleria fowleri in tap water from a US treated public drinking water system. Clin. Infect. Dis., 2015, 60, e36-e42.
Tiewcharoen, S.; Junnu, V.; Chinabut, P. In vitro effect of antifungal drugs on pathogenic Naegleria spp. Southeast Asian J. Trop. Med. Public Health, 2002, 33, 38-41.http://www.ncbi.nlm. (accessed November 28, 2018).
Debnath, A.; Tunac, J.B.; Galindo-Gómez, S.; Silva-Olivares, A.; Shibayama, M.; McKerrow, J.H. Corifungin, a new drug lead against Naegleria, identified from a high-throughput screen. Antimicrob. Agents Chemother., 2012, 56, 5450-5457.
Soltow, S.M.; Brenner, G.M. Synergistic activities of azithromycin and amphotericin B against Naegleria fowleri in vitro and in a mouse model of primary amebic meningoencephalitis. Antimicrob. Agents Chemother., 2007, 51, 23-27.
Rice, C.A.; Colon, B.L.; Alp, M.; Göker, H.; Boykin, D.W.; Kyle, D.E. Bis-Benzimidazole hits against Naegleria fowleri discovered with new high-throughput screens. Antimicrob. Agents Chemother., 2015, 59, 2037-2044.
Debnath, A.; Nelson, A.T.; Silva-Olivares, A.; Shibayama, M.; Siegel, D.; McKerrow, J.H. In vitro efficacy of ebselen and BAY 11-7082 against Naegleria fowleri. Front. Microbiol., 2018, 9, 414.
Carter, R.F. Sensitivity to amphotericin B of a Naegleria sp. isolated from a case of primary amoebic meningoencephalitis. J. Clin. Pathol., 1969, 22, 470-474.
Grace, E.; Asbill, S.; Virga, K. Naegleria fowleri: Pathogenesis, diagnosis, and treatment options. Antimicrob. Agents Chemother., 2015, 59, 6677-6681.
Goswick, S.M.; Brenner, G.M. Activities of azithromycin and amphotericin B against Naegleria fowleri in vitro and in a mouse model of primary amebic meningoencephalitis. Antimicrob. Agents Chemother., 2003, 47, 524-528.
Cárdenas-Zúñiga, R.; Silva-Olivares, A.; Villalba-Magdaleno, J.D.A.; Sánchez-Monroy, V.; Serrano-Luna, J.; Shibayama, M. Amphotericin B induces apoptosis-like programmed cell death in Naegleria fowleri and Naegleria gruberi. Microbiology, 2017, 163, 940-949.
Kim, J-H.; Jung, S-Y.; Lee, Y-J.; Song, K-J.; Kwon, D.; Kim, K. Park, S.; Im, K.-I.; Shin, H.-J. Effect of therapeutic chemical agents in vitro and on experimental meningoencephalitis due to Naegleriafowleri. Antimicrob. Agents Chemother., 2008, 52, 4010-4016.
Sau, K.; Mambula, S.S.; Latz, E.; Henneke, P.; Golenbock, D.T.; Levitz, S.M. The antifungal drug amphotericin B promotes inflammatory cytokine release by a Toll-like receptor and CD14-dependent mechanism. J. Biol. Chem., 2003, 278, 37561-37568.
Venegas, B.; González-Damián, J.; Celis, H.; Ortega-Blake, I. Amphotericin B channels in the bacterial membrane: Role of sterol and temperature. Biophys. J., 2003, 85, 2323-2332.
Rajendran, K.; Anwar, A.; Khan, N.A.; Siddiqui, R. Brain-eating amoebae: Silver nanoparticle conjugation enhanced efficacy of anti-amoebic drugs against Naegleria fowleri. ACS Chem. Neurosci., 2017, 8, 2626-2630.
Tyring, S.K.; Lupi, O.; Hengge, U.R. Tropical dermatology., Elsevier Churchill Livingstone,. 2006. books/about/Tropical_Dermatology.html?id=1_hsAAAAMAAJ&redir_esc=y (accessed November 28, 2018).
Schuster, F.L.; Visvesvara, G.S. Axenic growth and drug sensitivity studies of Balamuthia mandrillaris, an agent of amebic meningoencephalitis in humans and other animals. J. Clin. Microbiol., 1996, 34, 385-388. (accessed November 28, 2018).
Siddiqui, R.; Matin, A.; Warhurst, D.; Stins, M.; Khan, N.A. Effect of antimicrobial compounds on Balamuthia mandrillaris encystment and human brain microvascular endothelial cell cytopathogenicity. Antimicrob. Agents Chemother., 2007, 51, 4471-4473.
Kalsoom, H.; Baig, A.M.; Khan, N.A.; Siddiqui, R. Laboratory testing of clinically approved drugs against Balamuthia mandrillaris. World J. Microbiol. Biotechnol., 2014, 30, 2337-2342.
Laurie, M.T.; White, C.V.; Retallack, H.; Wu, W.; Moser, M.S.; Sakanari, J.A.; Ang, K.; Wilson, C.; Arkin, M.R.; DeRisi, J.L. Functional assessment of 2,177 U.S. and international drugs identifies the quinoline nitroxoline as a potent amoebicidal agent against the pathogen Balamuthia mandrillaris. MBio, 2018, 9, e02015-e02018.
Ghosh, P.; Han, G.; De, M.; Kim, C.K.; Rotello, V.M. Gold nanoparticles in delivery applications. Adv. Drug Deliv. Rev., 2008, 60, 1307-1315.
Chen, G.; Qiu, H.; Prasad, P.N.; Chen, X. Upconversion nanoparticles: design, nanochemistry, and applications in theranostics. Chem. Rev., 2014, 114, 5161-5214.
Singh, R.; James, W. Lillard Jr. Nanoparticle-based targeted drug delivery. Exp. Mol. Pathol., 2009, 86(3), 215-223.
Aqeel, Y.; Ruqaiyyah, S.; Ayaz, A.; Muhammad, R.S.; Naveed, A.K. Gold nanoparticle conjugation enhances the antiacanthamoebic effects of chlorhexidine. Antimicrob. Agents Chemother., 2016, 60(3), 1283-1288.
Anwar, A. et al Clinically approved drugs against CNS diseases as potential therapeutic agents to target brain-eating amoebae. ACS Chem. Neurosci., 2018, 10(1), 658-666.
Lemke, A. et al Delivery of amphotericin B nanosuspensions to the brain and determination of activity against Balamuthia mandrillaris amebas. Nanomedicine Nanotechnol. Biol. Med, 2010, 6(4), 597-603.
Anwar, A.; Siddiqui, R.; Khan, N.A. Importance of theranostics in rare brain-eating amoebae infections. ACS Chem. Neurosci., 2019, 10, 6-12.
Bissonnette, L.; Michel, G. Bergeron. Next revolution in the molecular theranostics of infectious diseases: microfabricated systems for personalized medicine. Expert Rev. Mol. Diagn., 2006, 6(3), 433-450.
López-Arencibia, A.; Reyes-Batlle, M. Freijo, M.B. McNaughton-Smith, G.; Martín-Rodríguez, P.; Fernández-Pérez, L.; Sifaoui, I. Wagner, C.; García-Méndez, A.B.; Liendo, A.R.; Bethencourt-Estrella, C.J. In vitro activity of 1H-phenalen-1-one derivatives against Acanthamoeba castellanii Neff and their mechanisms of cell death. Exp. Parasitol., 2017, 183, 218-223.

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