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  1. Drug modifications: graphene oxide-chitosan loading enhanced anti-amoebic effects of pentamidine and doxycycline
    Jabri T, Daalah M, Alawfi BS, Gul J, Ahmed U, Shah MR, et al.
    Parasitol Res, 2024 Nov 20;123(11):387.
    PMID: 39565414 DOI: 10.1007/s00436-024-08389-6
    Acanthamoeba castellanii is the causative pathogen of a severe eye infection, known as Acanthamoeba keratitis and a life-threatening brain infection, named granulomatous amoebic encephalitis. Current treatments are problematic and costly and exhibit limited efficacy against Acanthamoeba parasite, especially the cyst stage. In parallel to drug discovery and drug repurposing efforts, drug modification is also an important approach to tackle infections, especially against neglected parasites such as free-living amoebae: Acanthamoeba. In this study, we determined whether modifying pentamidine and doxycycline through chitosan-functionalized graphene oxide loading enhances their anti-amoebic effects. Various concentrations of doxycycline, pentamidine, graphene oxide, chitosan-functionalized graphene oxide, and chitosan-functionalized graphene oxide loaded with doxycycline and pentamidine were investigated for amoebicidal effects against pathogenic A. castellanii belonging to the T4 genotype. Lactate dehydrogenase assays were performed to determine toxic effects of these various drugs and nanoconjugates against human cells. The findings revealed that chitosan-functionalized graphene oxide loaded with doxycycline demonstrated potent amoebicidal effects. Nanomaterials significantly (p 
    Matched MeSH terms: Amebicides/pharmacology
  2. Fulltext Cobalt nanoparticles as novel nanotherapeutics against Acanthamoeba castellanii
    Anwar A, Numan A, Siddiqui R, Khalid M, Khan NA
    Parasit Vectors, 2019 Jun 03;12(1):280.
    PMID: 31159839 DOI: 10.1186/s13071-019-3528-2
    BACKGROUND: Species of Acanthamoeba are facultative pathogens which can cause sight threatening Acanthamoeba keratitis and a rare but deadly brain infection, granulomatous amoebic encephalitis. Due to conversion of Acanthamoeba trophozoites to resistant cyst stage, most drugs are found to be ineffective at preventing recurrence of infection. This study was designed to test the antiacanthamoebic effects of different cobalt nanoparticles (CoNPs) against trophozoites and cysts, as well as parasite-mediated host cell cytotoxicity.

    METHODS: Three different varieties of CoNPs were synthesized by utilizing hydrothermal and ultrasonication methods and were thoroughly characterized by X-ray diffraction and field emission scanning electron microscopy. Amoebicidal, encystation, excystation, and host cell cytopathogenicity assays were conducted to study the antiacanthamoebic effects of CoNPs.

    RESULTS: The results of the antimicrobial evaluation revealed that cobalt phosphate Co3(PO4)2 hexagonal microflakes, and 100 nm large cobalt hydroxide (Co(OH)2) nanoflakes showed potent amoebicidal activity at 100 and 10 µg/ml against Acanthamoeba castellanii as compared to granular cobalt oxide (Co3O4) of size 35-40 nm. Furthermore, encystation and excystation assays also showed consistent inhibition at 100 µg/ml. CoNPs also inhibited amoebae-mediated host cell cytotoxicity as determined by lactate dehydrogenase release without causing significant damage to human cells when treated alone.

    CONCLUSIONS: To our knowledge, these findings determined, for the first time, the effects of composition, size and morphology of CoNPs against A. castellanii. Co3(PO4)2 hexagonal microflakes showed the most promising antiamoebic effects as compared to Co(OH)2 nanoflakes and granular Co3O4. The results reported in the present study hold potential for the development of antiamoebic nanomedicine.

    Matched MeSH terms: Amebicides/pharmacology*
  3. Novel antiacanthamoebic compounds belonging to quinazolinones
    Anwar A, Shahbaz MS, Saad SM, Kanwal, Khan KM, Siddiqui R, et al.
    Eur J Med Chem, 2019 Nov 15;182:111575.
    PMID: 31415900 DOI: 10.1016/j.ejmech.2019.111575
    We report one-pot synthesis of a series of new 3-aryl-8-methylquinazolin-4(3H)-ones (QNZ) and their antimicrobial activity against Acanthamoeba castellanii belonging to T4 genotype. A library of fifteen synthetic derivatives of QNZs was synthesized, and their structural elucidation was performed by using nuclear magnetic resonance (NMR) spectroscopy and electron impact mass spectrometry (EI-MS). Elemental analyses and high-resolution mass spectrometry data of all derivatives were found to be in agreeable range. Amoebicidal assays performed at concentrations ranging from 50 to 100 μg/mL revealed that all derivatives of QNZ significantly decreased the viability of A. castellanii and QNZ 2, 5, 8, and 13 were found to have efficient antiamoebic effects. Field emission scanning electron microscopy (FESEM) imaging of amoeba treated with compounds 5 and 15 showed that these compounds cause structural alterations on the walls of A. castellanii. Furthermore, several QNZs inhibited the encystation and excystationas as well as abolished A. castellanii-mediated host cells cytopathogenicity in human cells. Whereas, these QNZs showed negligible cytotoxicity when tested against human cells in vitro. Hence, this study identified potential lead molecules having promising properties for drug development against A. castellanii. A brief structure-activity relationship is also developed to optimize the hit of most potent compounds from the library. To the best of our knowledge, it is first of its kind medicinal chemistry approach on a single class of compounds i.e., quinazolinone against keratitis and brain infection causing free-living amoeba, A. castellanii.
    Matched MeSH terms: Amebicides/pharmacology*
  4. Fulltext Amoebicidal activity of Cassia angustifolia extract and its effect on Acanthamoeba triangularis autophagy-related gene expression at the transcriptional level
    Boonhok R, Sangkanu S, Norouzi R, Siyadatpanah A, Mirzaei F, Mitsuwan W, et al.
    Parasitology, 2021 Aug;148(9):1074-1082.
    PMID: 33966667 DOI: 10.1017/S0031182021000718
    Cassia angustifolia Vahl. plant is used for many therapeutic purposes, for example, in people with constipation, skin diseases, including helminthic and parasitic infections. In our study, we demonstrated an amoebicidal activity of C. angustifolia extract against Acanthamoeba triangularis trophozoite at a micromolar level. Scanning electron microscopy (SEM) images displayed morphological changes in the Acanthamoeba trophozoite, which included the formation of pores in cell membrane and the membrane rupture. In addition to the amoebicidal activity, effects of the extract on surviving trophozoites were observed, which included cyst formation and vacuolization by a microscope and transcriptional expression of Acanthamoeba autophagy in response to the stress by quantitative polymerase chain reaction. Our data showed that the surviving trophozoites were not transformed into cysts and the trophozoite number with enlarged vacuole was not significantly different from that of untreated control. Molecular analysis data demonstrated that the mRNA expression of AcATG genes was slightly changed. Interestingly, AcATG16 decreased significantly at 12 h post treatment, which may indicate a transcriptional regulation by the extract or a balance of intracellular signalling pathways in response to the stress, whereas AcATG3 and AcATG8b remained unchanged. Altogether, these data reveal the anti-Acanthamoeba activity of C. angustifolia extract and the autophagic response in the surviving trophozoites under the plant extract pressure, along with data on the formation of cysts. These represent a promising plant for future drug development. However, further isolation and purification of an active compound and cytotoxicity against human cells are needed, including a study on the autophagic response at the protein level.
    Matched MeSH terms: Amebicides/pharmacology*
  5. Anti-Acanthamoebic effects of silver-conjugated tetrazole nanoparticle
    Anwar A, Fatima I, Khan KM, Daalah M, Alawfi BS, Khan NA, et al.
    Exp Parasitol, 2024 Oct;265:108827.
    PMID: 39147119 DOI: 10.1016/j.exppara.2024.108827
    Tetrazoles are five-membered ring aromatic heterocyclic molecules that consist of one carbon and four nitrogen atoms. Several tetrazole-based drugs have shown promising activities against bacteria, fungi, asthma, cancer, hypertension etc. The overall aim of this study was to determine anti-Acanthamoebic properties of tetrazoles and tetrazole-conjugated silver nanoparticles. Tetrazole-conjugated silver nanoparticles were synthesized and confirmed using ultraviolet-visible spectrometry, Dynamic light scattering, and Fourier-transform infrared spectroscopy. Using amoebicidal, encystment, and excystment assays, the findings revealed that tetrazoles exhibited antiamoebic properties and these effects were enhanced when conjugated with silver nanoparticles. Importantly, conjugation with silver nanoparticles inhibited parasite-mediated human cell death in vitro, as measured by lactate dehydrogenase release, but it reduced toxic effects of drugs alone on human cells. Overall, these results showed clearly that tetrazoles exhibit potent antiamoebic properties which can be enhanced by conjugation with silver nanoparticles and these potential in the rational development of therapeutic interventions against parasitic infections such as keratitis and granulomatous amoebic encephalitis due to pathogenic Acanthamoeba.
    Matched MeSH terms: Amebicides/pharmacology
  6. Metal Oxide Nanoparticles Exhibit Anti-Acanthamoeba castellanii Properties by Inducing Necrotic Cell Death
    Ahmed U, Gew LT, Siddiqui R, Khan NA, Alharbi AM, Alhazmi A, et al.
    Acta Parasitol, 2024 Sep;69(3):1717-1723.
    PMID: 39153011 DOI: 10.1007/s11686-024-00891-2
    PURPOSE: The treatment of amoebic infections is often problematic, largely due to delayed diagnosis, amoebae transformation into resistant cyst form, and lack of availability of effective chemotherapeutic agents. Herein, we determined anti-Acanthamoeba castellanii properties of three metal oxide nanoparticles (TiO2, ZrO2, and Al2O3).

    METHODS: Amoebicidal assays were performed to determine whether metal oxide nanoparticles inhibit amoebae viability. Encystation assays were performed to test whether metal oxide nanoparticles inhibit cyst formation. By measuring lactate dehydrogenase release, cytotoxicity assays were performed to determine human cell damage. Hoechst 33342/PI staining was performed to determine programmed cell death (apoptosis) and necrosis in A. castellanii.

    RESULTS: TiO2-NPs significantly inhibited amoebae viability as observed through amoebicidal assays, as well as inhibited their phenotypic transformation as evident using encystation assays, and showed limited human cell damage as observed by measuring lactate dehydrogenase assays. Furthermore, TiO2-NPs altered parasite membranes and resulted in necrotic cell death as determined using double staining cell death assays with Hoechst33342/Propidium iodide (PI) observed through chromatin condensation. These findings suggest that TiO2-NPs offers a potential viable avenue in the rationale development of therapeutic interventions against Acanthamoeba infections.

    Matched MeSH terms: Amebicides/pharmacology
  7. Fulltext In vitro drug susceptibility of Acanthamoeba castellani to chloroquine, ivermectin and fungizon
    Rain AN, Radzan T, Sajiri S, Mak JW
    Southeast Asian J Trop Med Public Health, 1996 Jun;27(2):319-24.
    PMID: 9279996
    In vitro sensitivity of Acanthamoeba castellani was tested to three drugs: Chloroquine, ivermectin and fungizone (amphotericin B). Sensitivity was demonstrated to the latter two compounds but not to chloroquine. Thus ivermectin and amphotericin B show promise as therapeutic agents against this parasite.
    Matched MeSH terms: Amebicides/pharmacology*
  8. Complete activation of autophagic process attenuates liver injury and improves survival in septic mice
    Lin CW, Lo S, Perng DS, Wu DB, Lee PH, Chang YF, et al.
    Shock, 2014 Mar;41(3):241-9.
    PMID: 24365881 DOI: 10.1097/SHK.0000000000000111
    The accumulation of autophagosomes in the terminal step of the autophagic process has recently emerged as a potentially maladaptive process in the septic heart and lung. However, the role of autophagy in the septic liver has not been ascertained. This study was investigated by first examining the entire sequence of the autophagic process in the liver of septic mice. Second, a novel pharmacotherapeutic approach was utilized to treat sepsis with autophagy enhancer/inhibitor. Sepsis was induced by cecal ligation and puncture (CLP). C57BL/6 mice received autophagy enhancer carbamazepine (CBZ), autophagy inhibitor 3-methyladenine (inhibition of autophagosomal formation), or chloroquine (impairment of autophagosomal clearance). We found that the whole autophagic process was activated at 4 h after CLP; however, it did not proceed to completion during the 4- to 24-h time period, as indicated by accumulated autophagosomes and decreased autophagic flux. Carbamazepine, which induced complete activation of the autophagic process, improved CLP survival. This protective effect was also associated with decreased cell death, inflammatory responses, and hepatic injury. However, disruption of autophagosomal clearance with chloroquine abolished the above protective effects in CBZ-treated CLP mice. 3-Methyladenine, which resulted in inhibition of the autophagosomal formation, did not show any above beneficial effects in CLP mice. Impaired autophagosome-lysome fusion resulting in incomplete activation of autophagy may contribute to sepsis-induced liver injury. Treatment with CBZ may serve a protective role in the septic liver, possibly through the effect of complete activation of autophagic process.
    Matched MeSH terms: Amebicides/pharmacology
  9. Fulltext Antidiabetic Drugs and Their Nanoconjugates Repurposed as Novel Antimicrobial Agents against Acanthamoeba castellanii
    Anwar A, Siddiqui R, Raza Shah M, Khan NA
    J Microbiol Biotechnol, 2019 May 28;29(5):713-720.
    PMID: 31030451 DOI: 10.4014/jmb/1903.03009
    Acanthamoeba castellanii belonging to the T4 genotype may cause a fatal brain infection known as granulomatous amoebic encephalitis, and the vision-threatening eye infection Acanthamoeba keratitis. The aim of this study was to evaluate the antiamoebic effects of three clinically available antidiabetic drugs, Glimepiride, Vildagliptin and Repaglinide, against A. castellanii belonging to the T4 genotype. Furthermore, we attempted to conjugate these drugs with silver nanoparticles (AgNPs) to enhance their antiamoebic effects. Amoebicidal, encystation, excystation, and host cell cytotoxicity assays were performed to unravel any antiacanthamoebic effects. Vildagliptin conjugated silver nanoparticles (Vgt-AgNPs) characterized by spectroscopic techniques and atomic force microscopy were synthesized. All three drugs showed antiamoebic effects against A. castellanii and significantly blocked the encystation. These drugs also showed significant cysticidal effects and reduced host cell cytotoxicity caused by A. castellanii. Moreover, Vildagliptin-coated silver nanoparticles were successfully synthesized and are shown to enhance its antiacanthamoebic potency at significantly reduced concentration. The repurposed application of the tested antidiabetic drugs and their nanoparticles against free-living amoeba such as Acanthamoeba castellanii described here is a novel outcome that holds tremendous potential for future applications against devastating infection.
    Matched MeSH terms: Amebicides/pharmacology*
  10. Fulltext PLGA nanoparticles loaded with Gallic acid- a constituent of Leea indica against Acanthamoeba triangularis
    Mahboob T, Nawaz M, de Lourdes Pereira M, Tian-Chye T, Samudi C, Sekaran SD, et al.
    Sci Rep, 2020 06 02;10(1):8954.
    PMID: 32488154 DOI: 10.1038/s41598-020-65728-0
    Acanthamoeba, a genus that contains at least 24 species of free-living protozoa, is ubiquitous in nature. Successful treatment of Acanthamoeba infections is always very difficult and not always effective. More effective drugs must be developed, and medicinal plants may have a pivotal part in the future of drug discovery. Our research focused on investigating the in vitro anti- acanthamoebic potential of Leea indica and its constituent gallic acid in different concentrations. Water and butanol fractions exhibited significant amoebicidal activity against trophozoites and cysts. Gallic acid (100 µg/mL) revealed 83% inhibition of trophozoites and 69% inhibition of cysts. The butanol fraction induced apoptosis in trophozoites, which was observed using tunnel assay. The cytotoxicity of the fractions and gallic acid was investigated against MRC-5 and no adverse effects were observed. Gallic acid was successfully loaded within poly (D,L-lactide-co-glycolide) (PLGA) nanoparticles with 82.86% encapsulation efficiency, while gallic acid showed 98.24% in vitro release at 48 hours. Moreover, the gallic acid encapsulated in the PLGA nanoparticles exhibited 90% inhibition against trophozoites. In addition, gallic acid encapsulated nanoparticles showed reduced cytotoxicity towards MRC-5 compared to gallic acid, which evidenced that natural product nanoencapsulation in polymeric nanoparticles could play an important role in the delivery of natural products.
    Matched MeSH terms: Amebicides/pharmacology
  11. Fulltext Gold Nanoparticle-Conjugated Cinnamic Acid Exhibits Antiacanthamoebic and Antibacterial Properties
    Anwar A, Siddiqui R, Shah MR, Khan NA
    Antimicrob Agents Chemother, 2018 09;62(9).
    PMID: 29967024 DOI: 10.1128/AAC.00630-18
    trans-Cinnamic acid (CA) is a natural organic compound. Using amoebicidal assays, for the first time we showed that CA affected the viability of the protist pathogen Acanthamoeba castellanii Conjugation with gold nanoparticles (AuNPs) enhanced the antiamoebic effects of CA. CA-coated AuNPs (CA-AuNPs) also exhibited significant excystation and encystation activity, compared to CA and AuNPs alone. Pretreatment of amoebae with CA-AuNPs inhibited A. castellanii-mediated host cell cytotoxicity. Moreover, CA-AuNPs exhibited potent effects against methicillin-resistant Staphylococcus aureus and neuropathogenic Escherichia coli K1 and protected host cells against bacteria-mediated host cell death.
    Matched MeSH terms: Amebicides/pharmacology*
  12. Clinically Approved Drugs against CNS Diseases as Potential Therapeutic Agents To Target Brain-Eating Amoebae
    Anwar A, Rajendran K, Siddiqui R, Raza Shah M, Khan NA
    ACS Chem Neurosci, 2019 01 16;10(1):658-666.
    PMID: 30346711 DOI: 10.1021/acschemneuro.8b00484
    Central nervous system (CNS) infections caused by free-living amoebae such as Acanthamoeba species and Naegleria fowleri are rare but fatal. A major challenge in the treatment against the infections caused by these amoebae is the discovery of novel compounds that can effectively cross the blood-brain barrier to penetrate the CNS. It is logical to test clinically approved drugs against CNS diseases for their potential antiamoebic effects since they are known for effective blood-brain barrier penetration and affect eukaryotic cell targets. The antiamoebic effects of clinically available drugs for seizures targeting gamma-amino butyric acid (GABA) receptor and ion channels were tested against Acanthamoeba castellanii belonging to the T4 genotype and N. fowleri. Three such drugs, namely, diazepam (Valium), phenobarbitone (Luminal), phenytoin (Dilantin), and their silver nanoparticles (AgNPs) were evaluated against both trophozoites and cysts stage. Drugs alone and drug conjugated silver nanoparticles were tested for amoebicidal, cysticidal, and host-cell cytotoxicity assays. Nanoparticles were synthesized by sodium borohydride reduction of silver nitrate with drugs as capping agents. Drug conjugated nanoconjugates were characterized by ultraviolet-visible (UV-vis) and Fourier transform infrared (FT-IR) spectroscopies and atomic force microscopy (AFM). In vitro moebicidal assay showed potent amoebicidal effects for diazepam, phenobarbitone, and phenytoin-conjugated AgNPs as compared to drugs alone against A. castellanii and N. fowleri. Furthermore, both drugs and drug conjugated AgNPs showed compelling cysticidal effects. Drugs conjugations with silver nanoparticles enhanced their antiacanthamoebic activity. Interestingly, amoeba-mediated host-cell cytotoxicity was also significantly reduced by drugs alone as well as their nanoconjugates. Since, these drugs are being used to target CNS diseases, their evaluation against brain-eating amoebae seems feasible due to advantages such as permeability of the blood-brain barrier, established pharmacokinetics and dynamics, and United States Food and Drug Administration (FDA) approval. Given the limited availability of effective drugs against brain-eating amoebae, the clinically available drugs tested here present potential for further in vivo studies.
    Matched MeSH terms: Amebicides/pharmacology*
  13. Oleic acid-conjugated silver nanoparticles as efficient antiamoebic agent against Acanthamoeba castellanii
    Anwar A, Abdalla SAO, Aslam Z, Shah MR, Siddiqui R, Khan NA
    Parasitol Res, 2019 Jul;118(7):2295-2304.
    PMID: 31093751 DOI: 10.1007/s00436-019-06329-3
    Acanthamoeba castellanii belonging to the T4 genotype is an opportunistic pathogen which is associated with blinding eye keratitis and rare but fatal central nervous system infection. A. castellanii pose serious challenges in antimicrobial chemotherapy due to its ability to convert into resistant, hardy shell-protected cyst form that leads to infection recurrence. The fatty acid composition of A. castellanii trophozoites is known to be most abundant in oleic acid which chemically is an unsaturated cis-9-Octadecanoic acid and naturally found in animal and vegetable fats and oils. This study was designed to evaluate antiacanthamoebic effects of oleic acid against trophozoites, cysts as well as parasite-mediated host cell cytotoxicity. Moreover, oleic acid-conjugated silver nanoparticles (AgNPs) were also synthesized and tested against A. castellanii. Oleic acid-AgNPs were synthesized by chemical reduction method and characterized by ultraviolet-visible spectrophotometry, atomic force microscopy, dynamic light scattering analysis, and Fourier transform infrared spectroscopy. Viability, growth inhibition, encystation, and excystation assays were performed with 10 and 5 μM concentration of oleic acid alone and oleic acid-conjugated AgNPs. Bioassays revealed that oleic acid alone and oleic acid-conjugated AgNPs exhibited significant antiamoebic properties, whereas nanoparticle conjugation further enhanced the efficacy of oleic acid. Phenotype differentiation assays also showed significant inhibition of encystation and excystation at 5 μM. Furthermore, oleic acid and oleic acid-conjugated AgNPs also inhibited amoebae-mediated host cell cytotoxicity as determined by lactate dehydrogenase release. These findings for the first time suggest that oleic acid-conjugated AgNPs exhibit antiacanthamoebic activity that hold potential for therapeutic applications against A. castellanii.
    Matched MeSH terms: Amebicides/pharmacology*
  14. Antiamoebic activity of 3-aryl-6,7-dimethoxyquinazolin-4(3H)-one library against Acanthamoeba castellanii
    Shahbaz MS, Anwar A, Saad SM, Kanwal, Anwar A, Khan KM, et al.
    Parasitol Res, 2020 Jul;119(7):2327-2335.
    PMID: 32476058 DOI: 10.1007/s00436-020-06710-7
    Acanthamoeba castellanii is a free-living amoeba which can cause a blinding keratitis and fatal granulomatous amoebic encephalitis. The treatment of Acanthamoeba infections is challenging due to formation of cyst. Quinazolinones are medicinally important scaffold against parasitic diseases. A library of nineteen new 3-aryl-6,7-dimethoxyquinazolin-4(3H)-one derivatives was synthesized to evaluate their antiamoebic activity against Acanthamoeba castellanii. One-pot synthesis of 3-aryl-6,7-dimethoxyquinazolin-4(3H)-ones (1-19) was achieved by reaction of 2-amino-4,5-dimethoxybenzoic acid, trimethoxymethane, and different substituted anilines. These compounds were purified and characterized by standard chromatographic and spectroscopic techniques. Antiacanthamoebic activity of these compounds was determined by amoebicidal, encystation, excystation and host cell cytopathogenicity in vitro assays at concentrations of 50 and 100 μg/mL. The IC50 was found to be between 100 and 50 μg/mL for all the compounds except compound 5 which did not exhibit amoebicidal effects at these concentrations. Furthermore, lactate dehydrogenase assay was also performed to evaluate the in vitro cytotoxicity of these compounds against human keratinocyte (HaCaT) cells. The results revealed that eighteen out of nineteen derivatives of quinazolinones significantly decreased the viability of A. castellanii. Furthermore, eighteen out of nineteen tested compounds inhibited the encystation and excystation, as well as significantly reduced the A. castellanii-mediated cytopathogenicity against human cells. Interestingly, while tested against human normal cell line HaCaT keratinocytes, all compounds did not exhibit any overt cytotoxicity. Furthermore, a detailed structure-activity relationship is also studied to optimize the most potent hit from these synthetic compounds. This report presents several potential lead compounds belonging to 3-aryl-6,7-dimethoxyquinazolin-4(3H)-one derivatives for drug discovery against infections caused by Acanthamoeba castellanii.
    Matched MeSH terms: Amebicides/pharmacology*
  15. Antiamoebic activity of synthetic tetrazoles against Acanthamoeba castellanii belonging to T4 genotype and effects of conjugation with silver nanoparticles
    Anwar A, Yi YP, Fatima I, Khan KM, Siddiqui R, Khan NA, et al.
    Parasitol Res, 2020 Jun;119(6):1943-1954.
    PMID: 32385711 DOI: 10.1007/s00436-020-06694-4
    Acanthamoeba causes diseases such as Acanthamoeba keratitis (AK) which leads to permanent blindness and granulomatous Acanthamoeba encephalitis (GAE) where there is formation of granulomas in the brain. Current treatments such as chlorhexidine, diamidines, and azoles either exhibit undesirable side effects or require immediate and prolonged treatment for the drug to be effective or prevent relapse. Previously, antifungal drugs amphotericin B, nystatin, and fluconazole-conjugated silver with nanoparticles have shown significantly increased activity against Acanthamoeba castellanii. In this study, two functionally diverse tetrazoles were synthesized, namely 5-(3-4-dimethoxyphenyl)-1H-tetrazole and 1-(3-methoxyphenyl)-5-phenoxy-1H-tetrazole, denoted by T1 and T2 respectively. These compounds were evaluated for anti-Acanthamoeba effects at different concentrations ranging from 5 to 50 μM. Furthermore, these compounds were conjugated with silver nanoparticles (AgNPs) to enhance their efficacy. Particle size analysis showed that T1-AgNPs and T2-AgNPs had an average size of 52 and 70 nm respectively. After the successful synthesis and characterization of tetrazoles and tetrazole-conjugated AgNPs, they were subjected to anti-Acanthamoeba studies. Amoebicidal assay showed that at concentration 10 μM and above, T2 showed promising antiamoebic activities between the two compounds while encystation and excystation assays reveal that both T1 and T2 have inhibited differentiation activity against Acanthamoeba castellanii. Conjugation of T1 and T2 to AgNP also increased efficacy of tetrazoles as anti-Acanthamoeba agents. This may be due to the increased bioavailability as AgNP allows better delivery of treatment compounds to A. castellanii. Human cell cytotoxicity assay revealed that tetrazoles and AgNPs are significantly less toxic towards human cells compared with chlorhexidine which is known to cause undesirable side effects. Cytopathogenicity assay also revealed that T2 conjugated with AgNPs significantly reduced cytopathogenicity of A. castellanii compared with T2 alone, suggesting that T2-conjugated AgNP is an effective and safe anti-Acanthamoeba agent. The use of a synthetic azole compound conjugated with AgNPs can be an alternative strategy for drug development against A. castellanii. However, mechanistic and in vivo studies are needed to explore further translational values.
    Matched MeSH terms: Amebicides/pharmacology*
  16. Silver nanoparticle conjugation affects antiacanthamoebic activities of amphotericin B, nystatin, and fluconazole
    Anwar A, Siddiqui R, Hussain MA, Ahmed D, Shah MR, Khan NA
    Parasitol Res, 2018 Jan;117(1):265-271.
    PMID: 29218442 DOI: 10.1007/s00436-017-5701-x
    Infectious diseases are the leading cause of morbidity and mortality, killing more than 15 million people worldwide. This is despite our advances in antimicrobial chemotherapy and supportive care. Nanoparticles offer a promising technology to enhance drug efficacy and formation of effective vehicles for drug delivery. Here, we conjugated amphotericin B, nystatin (macrocyclic polyenes), and fluconazole (azole) with silver nanoparticles. Silver-conjugated drugs were synthesized successfully and characterized by ultraviolet-visible spectrophotometry, Fourier transform infrared spectroscopy, and atomic force microscopy. Conjugated and unconjugated drugs were tested against Acanthamoeba castellanii belonging to the T4 genotype using amoebicidal assay and host cell cytotoxicity assay. Viability assays revealed that silver nanoparticles conjugated with amphotericin B (Amp-AgNPs) and nystatin (Nys-AgNPs) exhibited significant antiamoebic properties compared with drugs alone or AgNPs alone (P 
    Matched MeSH terms: Amebicides/pharmacology*
  17. Anti-amoebic activity of acyclic and cyclic-samarium complexes on Acanthamoeba
    Kusrini E, Hashim F, Gunawan C, Mann R, Azmi WNNWN, Amin NM
    Parasitol Res, 2018 May;117(5):1409-1417.
    PMID: 29532220 DOI: 10.1007/s00436-018-5814-x
    This work investigated the anti-amoebic activity of two samarium (Sm) complexes, the acyclic complex [bis(picrato)(pentaethylene glycol)samarium(III)] picrate-referred to as [Sm(Pic)2(EO5)](Pic)-and the cyclic complex [bis(picrato)(18-crown-6)samarium(III)] picrate-referred to as [Sm(Pic)2(18C6)](Pic). Both Sm complexes caused morphological transformation of the protozoa Acanthamoeba from its native trophozoite form carrying a spine-like structure called acanthopodia, to round-shaped cells with loss of the acanthopodia structure, a trademark response to environmental stress. Further investigation, however, revealed that the two forms of the Sm complexes exerted unique cytotoxicity characteristics. Firstly, the IC50 of the acyclic complex (0.7 μg/mL) was ~ 10-fold lower than IC50 of the cyclic Sm complex (6.5 μg/mL). Secondly, treatment of the Acanthamoeba with the acyclic complex caused apoptosis of the treated cells, while the treatment with the cyclic complex caused necrosis evident by the leakage of the cell membrane. Both treatments induced DNA damage in Acanthamoeba. Finally, a molecular docking simulation revealed the potential capability of the acyclic complex to form hydrogen bonds with profilin-a membrane protein present in eukaryotes, including Acanthamoeba, that plays important roles in the formation and degradation of actin cytoskeleton. Not found for the cyclic complex, such potential interactions could be the underlying reason, at least in part, for the much higher cytotoxicity of the acyclic complex and also possibly, for the observed differences in the cytotoxicity traits. Nonetheless, with IC50 values of
    Matched MeSH terms: Amebicides/pharmacology*
  18. Repositioning of Guanabenz in Conjugation with Gold and Silver Nanoparticles against Pathogenic Amoebae Acanthamoeba castellanii and Naegleria fowleri
    Anwar A, Mungroo MR, Anwar A, Sullivan WJ, Khan NA, Siddiqui R
    ACS Infect Dis, 2019 Dec 13;5(12):2039-2046.
    PMID: 31612700 DOI: 10.1021/acsinfecdis.9b00263
    Brain-eating amoebae cause devastating infections in the central nervous system of humans, resulting in a mortality rate of 95%. There are limited effective therapeutic options available clinically for treating granulomatous amoebic encephalitis and primary amoebic meningoencephalitis caused by Acanthamoeba castellanii (A. castellanii) and Naegleria fowleri (N. fowleri), respectively. Here, we report for the first time that guanabenz conjugated to gold and silver nanoparticles has significant antiamoebic activity against both A. castellanii and N. fowleri. Gold and silver conjugated guanabenz nanoparticles were synthesized by the one-phase reduction method and were characterized by ultraviolet-visible spectrophotometry and atomic force microscopy. Both metals were facilely stabilized by the coating of guanabenz, which was examined by surface plasmon resonance determination. The average size of gold nanoconjugated guanabenz was found to be 60 nm, whereas silver nanoparticles were produced in a larger size distribution with the average diameter of around 100 nm. Guanabenz and its noble metal nanoconjugates exhibited potent antiamoebic effects in the range of 2.5 to 100 μM against both amoebae. Nanoparticle conjugation enhanced the antiamoebic effects of guanabenz, as more potent activity was observed at a lower effective concentration (2.5 and 5 μM) compared to the drug alone. Moreover, encystation and excystation assays revealed that guanabenz inhibits the interconversion between the trophozoite and cyst forms of A. castellanii. Cysticdal effects against N. fowleri were also observed. Notably, pretreatment of A. castellanii with guanabenz and its nanoconjugates exhibited a significant reduction in the host cell cytopathogenicity from 65% to 38% and 2% in case of gold and silver nanoconjugates, respectively. Moreover, the cytotoxic evaluation of guanabenz and its nanoconjugates revealed negligible cytotoxicity against human cells. Guanabenz is already approved for hypertension and crosses the blood-brain barrier; the results of our current study suggest that guanabenz and its conjugated gold and silver nanoparticles can be repurposed as a potential drug for treating brain-eating amoebic infections.
    Matched MeSH terms: Amebicides/pharmacology
  19. Crocodiles and alligators: Antiamoebic and antitumor compounds of crocodiles
    Siddiqui R, Jeyamogan S, Ali SM, Abbas F, Sagathevan KA, Khan NA
    Exp Parasitol, 2017 Dec;183:194-200.
    PMID: 28917711 DOI: 10.1016/j.exppara.2017.09.008
    Crocodiles exist in unsanitary environments, feed on rotten meat, are often exposed to heavy metals such as arsenic, cadmium, cobalt, chromium, mercury, nickel, lead, selenium, tolerate high levels of radiation, and are amid the very few species to survive the catastrophic Cretaceous-Tertiary extinction event, nonetheless they can live for up to a 100 years. Moreover, as they live in unhygienic conditions, they regularly come across pathogens. Logically, we postulate that crocodiles possess mechanisms to defend themselves from noxious agents as well as protecting themselves from pathogens. To test this hypothesis, various organ lysates and serum of Crocodylus palustris were prepared. Amoebicidal assays were performed using Acanthamoeba castellanii belonging to the T4 genotype. Cytotoxicity assays were performed using Prostate cancer cells culture by measuring lactate dehydrogenase release as a marker for cell death. Growth inhibition assays were performed to determine the growth inhibitory effects of various organ lysates. Serum and heart lysates of Crocodylus palustris exhibited powerful anti-tumor activity exhibiting more than 70% Prostate cancer cell death (P 
    Matched MeSH terms: Amebicides/pharmacology*
  20. Fulltext Antimicrobial activities of green synthesized gums-stabilized nanoparticles loaded with flavonoids
    Anwar A, Masri A, Rao K, Rajendran K, Khan NA, Shah MR, et al.
    Sci Rep, 2019 02 28;9(1):3122.
    PMID: 30816269 DOI: 10.1038/s41598-019-39528-0
    Herein, we report green synthesized nanoparticles based on stabilization by plant gums, loaded with citrus fruits flavonoids Hesperidin (HDN) and Naringin (NRG) as novel antimicrobial agents against brain-eating amoebae and multi-drug resistant bacteria. Nanoparticles were thoroughly characterized by using zetasizer, zeta potential, atomic force microscopy, ultravoilet-visible and Fourier transform-infrared spectroscopic techniques. The size of these spherical nanoparticles was found to be in the range of 100-225 nm. The antiamoebic effects of these green synthesized Silver and Gold nanoparticles loaded with HDN and NRG were tested against Acanthamoeba castellanii and Naegleria fowleri, while antibacterial effects were evaluated against methicillin-resistant Staphylococcus aureus (MRSA) and neuropathogenic Escherichia coli K1. Amoebicidal assays revealed that HDN loaded Silver nanoparticles stabilized by gum acacia (GA-AgNPs-HDN) quantitatively abolished amoeba viability by 100%, while NRG loaded Gold nanoparticles stabilized by gum tragacanth (GT-AuNPs-NRG) significantly reduced the viability of A. castellanii and N. fowleri at 50 µg per mL. Furthermore, these nanoparticles inhibited the encystation and excystation by more than 85%, as well as GA-AgNPs-HDN only completely obliterated amoeba-mediated host cells cytopathogenicity. Whereas, GA-AgNPs-HDN exhibited significant bactericidal effects against MRSA and E. coli K1 and reduced bacterial-mediated host cells cytotoxicity. Notably, when tested against human cells, these nanoparticles showed minimal (23%) cytotoxicity at even higher concentration of 100 µg per mL as compared to 50 µg per mL used for antimicrobial assays. Hence, these novel nanoparticles formulations hold potential as therapeutic agents against infections caused by brain-eating amoebae, as well as multi-drug resistant bacteria, and recommend a step forward in drug development.
    Matched MeSH terms: Amebicides/pharmacology
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