Innovative Methodology in the Discovery of Novel Drug Targets in the Free-Living Amoebae

Author(s): Abdul Mannan Baig*.

Journal Name: Current Drug Targets

Volume 20 , Issue 1 , 2019

  Journal Home
Translate in Chinese
Become EABM
Become Reviewer

Graphical Abstract:


Abstract:

Despite advances in drug discovery and modifications in the chemotherapeutic regimens, human infections caused by free-living amoebae (FLA) have high mortality rates (~95%). The FLA that cause fatal human cerebral infections include Naegleria fowleri, Balamuthia mandrillaris and Acanthamoeba spp. Novel drug-target discovery remains the only viable option to tackle these central nervous system (CNS) infection in order to lower the mortality rates caused by the FLA. Of these FLA, N. fowleri causes primary amoebic meningoencephalitis (PAM), while the A. castellanii and B. Mandrillaris are known to cause granulomatous amoebic encephalitis (GAE). The infections caused by the FLA have been treated with drugs like Rifampin, Fluconazole, Amphotericin-B and Miltefosine. Miltefosine is an anti-leishmanial agent and an experimental anti-cancer drug. With only rare incidences of success, these drugs have remained unsuccessful to lower the mortality rates of the cerebral infection caused by FLA. Recently, with the help of bioinformatic computational tools and the discovered genomic data of the FLA, discovery of newer drug targets has become possible. These cellular targets are proteins that are either unique to the FLA or shared between the humans and these unicellular eukaryotes. The latter group of proteins has shown to be targets of some FDA approved drugs prescribed in non-infectious diseases. This review out-lines the bioinformatics methodologies that can be used in the discovery of such novel drug-targets, their chronicle by in-vitro assays done in the past and the translational value of such target discoveries in human diseases caused by FLA.

Keywords: Drug target discovery, free-living amoeba, Acanthamoeba, Naegleria fowleri, Balamuthia mandrillaris, structure activity relationship.

[1]
Visvesvara GS, Moura H, Schuster FL. Pathogenic and opportunistic free-living amoebae: Acanthamoeba spp., Balamuthia mandrillaris, Naegleria fowleri, and Sappinia diploidea. FEMS Immunol Med Microbiol 2007; 50(1): 1-26.
[2]
Fabres LF, Rosa Dos Santos SP, Benitez LB, Rott MB. Isolation and identification of Acanthamoeba spp. from thermal swimming pools and spas in Southern Brazil. Acta Parasitol 2016; 61(2): 221-7.
[3]
Khan NA. Acanthamoeba: biology and increasing importance in human health. FEMS Microbiol Rev 2006; 30: 564-95.
[4]
Baig AM. Primary Amoebic Meningoencephalitis: neurochemotaxis and neurotropic preferences of Naegleria fowleri. ACS Chem Neurosci 2016; 7(8): 1026-9.
[5]
Baig AM, Khan NA. A proposed cascade of vascular events leading to granulomatous amoebic encephalitis. Microb Pathog 2015; 88: 48-51.
[6]
Pugh JJ, Levy RA. Naegleria fowleri: Diagnosis, pathophysiology of brain inflammation, and antimicrobial treatments. ACS Chem Neurosci 2016; 7(9): 1178-9.
[7]
Stevens AR, O’Dell WD. In vitro and in vivo activity of 5-fluorocytosine on Acanthamoeba. Antimicrob Agents Chemother 1974; 6(3): 282-9.
[8]
Maritschnegg P, Sovinz P, Lackner H, et al. Granulomatous amebic encephalitis in a child with acute lymphoblastic leukemia successfully treated with multimodal antimicrobial therapy and hyperbaric oxygen. J Clin Microbiol 2011; 49: 446-8.
[9]
Baig AM. Pathogenesis of amoebic encephalitis: Are the amoebae being credited to an ‘inside job’ done by the host immune response? Acta Trop 2015; 148: 72-6.
[10]
Trösken ER, Adamska M, Arand M, et al. Comparison of lanosterol-14 alpha-demethylase (CYP51) of human and Candida albicans for inhibition by different antifungal azoles. Toxicology 2006; 228(1): 24-32.
[11]
Lamb DC1, Kelly DE, Baldwin BC, Kelly SL. Differential inhibition of human CYP3A4 and Candida albicans CYP51 with azole antifungal agents. Chem Biol Interact 2000; 125(3): 165-75.
[12]
Dunn AL, Reed T, Stewart C, Levy RA. Naegleria fowleri that induces primary amoebic meningoencephalitis: Rapid diagnosis and rare case of survival in a 12-year-old caucasian girl. Lab Med 2016; 47(2): 149-54.
[13]
Schuster FL, Mandel N. Phenothiazine compounds inhibit in vitro growth of pathogenic free-living amoebae. Antimicrob Agents Chemother 1984; 25(1): 109-12.
[14]
Kim JH, Jung SY, Lee YJ, et al. Effect of therapeutic chemical agents in vitro and on experimental meningoencephalitis due to Naegleria fowleri. Antimicrob Agents Chemother 2008; 52(11): 4010-6.
[15]
Baig AM, Iqbal J, Khan NA. In vitro efficacies of clinically available drugs against growth and viability of an Acanthamoeba castellanii keratitis isolate belonging to the T4 genotype. Antimicrob Agents Chemother 2013; 57(8): 3561-7.
[16]
Kulsoom H, Baig AM, Siddiqui R, Khan NA. Combined drug therapy in the management of granulomatous amoebic encephalitis due to Acanthamoeba spp., and Balamuthia mandrillaris. Exp Parasitol 2014; 145(Suppl.): S115-20.
[17]
Agahan AL, Lim RB, Valenton MJ. Successful treatment of Acanthamoeba keratitis without anti-amoebic agents. Ann Acad Med Singapore 2009; 38: 175-6.
[18]
Baig AM, Zuberi H, Khan NA. Recommendations for the management of Acanthamoeba keratitis. J Med Microbiol 2014; 63(Pt 5): 770-1.
[19]
Baig AM, Rana Z, Tariq S, Lalani S, Ahmad HR. Traced on the timeline: Discovery of acetylcholine and the components of the human cholinergic system in a primitive unicellular eukaryote Acanthamoeba spp. ACS Chem Neurosci 2018; 9(3): 494-504.
[20]
Brunton LL, Chabner BA, Knollman BC. Goodman and Gilman’s The pharmacological basis of therapeutics, 12th ed McGraw-Hill, NewYork, NY 2011.
[21]
Rajendran K, Anwar A, Khan NA, Siddiqui R. Brain-eating amoebae: silver nanoparticle conjugation enhanced efficacy of anti-amoebic drugs against naegleria fowleri. ACS Chem Neurosci 2017; 8(12): 2626-30.
[22]
Baig AM, Rana Z, Tariq SS, Ahmad HR. Bioinformatic insights on target receptors of amiodarone in human and Acanthamoeba castellanii. Infect Disord Drug Targets 2017; 17(3): 160-77.
[23]
Cai X. Ancient origin of four-domain voltage-gated Na+ channels predates the divergence of animals and fungi. J Membr Biol 2012; 245: 117-23.
[24]
Baig AM, Zohaib R, Tariq S, Ahmad HR. Evolution of pH buffers and water homeostasis in eukaryotes: homology between humans and Acanthamoeba proteins. Future Microbiol 2018; 13: 195-207.
[25]
Baig AM, Ahmad HR. Evidence of a M(1)-muscarinic GPCR homolog in unicellular eukaryotes: featuring Acanthamoeba spp bioinformatics 3D-modelling and experimentations. J Recept Signal Transduct Res 2017; 37(3): 267-75.
[26]
Baig AM, Rana Z, Mannan M, Tariq S, Ahmad HR. Antibiotic Effects of Loperamide: Homology of Human Targets of Loperamide with Targets in Acanthamoeba spp. Recent Pat Antiinfect Drug Discov 2017; 12(1): 44-60.
[27]
Clarke M, Lohan AJ, Liu B, et al. Genome of Acanthamoeba castellanii highlights extensive lateral gene transfer and Early evolution of tyrosine kinase signaling. Genome Biol 2013; 14(2): R11.
[28]
Schneidman-Duhovny D, Inbar Y, Nussinov R, Wolfson HJ. PatchDock and SymmDock: servers for rigid and symmetric docking Nucleic Acids Res 2005; 33(Web Server issue): W363-7
[29]
Wallace AC, Laskowski RA, Thornton JM. LIGPLOT: A program to generate schematic diagrams of protein-ligand interactions. Protein Eng 1995; 8(2): 127-34.


Rights & PermissionsPrintExport Cite as

Article Details

VOLUME: 20
ISSUE: 1
Year: 2019
Page: [60 - 69]
Pages: 10
DOI: 10.2174/1389450119666180426100452
Price: $58

Article Metrics

PDF: 24
HTML: 5