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Anti-Balamuthia mandrillaris and anti-Naegleria fowleri effects of drugs conjugated with various nanostructures

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Abstract

Balamuthia mandrillaris and Naegleria fowleri are protist pathogens that can cause fatal infections. Despite mortality rate of > 90%, there is no effective therapy. Treatment remains problematic involving repurposed drugs, e.g., azoles, amphotericin B and miltefosine but requires early diagnosis. In addition to drug discovery, modifying existing drugs using nanotechnology offers promise in the development of therapeutic interventions against these parasitic infections. Herein, various drugs conjugated with nanoparticles were developed and evaluated for their antiprotozoal activities. Characterizations of the drugs’ formulations were accomplished utilizing Fourier-transform infrared spectroscopy, efficiency of drug entrapment, polydispersity index, zeta potential, size, and surface morphology. The nanoconjugates were tested against human cells to determine their toxicity in vitro. The majority of drug nanoconjugates exhibited amoebicidal effects against B. mandrillaris and N. fowleri. Amphotericin B-, Sulfamethoxazole-, Metronidazole-based nanoconjugates are of interest since they exhibited significant amoebicidal effects against both parasites (p < 0.05). Furthermore, Sulfamethoxazole and Naproxen significantly diminished host cell death caused by B. mandrillaris by up to 70% (p < 0.05), while Amphotericin B-, Sulfamethoxazole-, Metronidazole-based drug nanoconjugates showed the highest reduction in host cell death caused by N. fowleri by up to 80%. When tested alone, all of the drug nanoconjugates tested in this study showed limited toxic effects against human cells in vitro (less than 20%). Although these are promising findings, prospective work is warranted to comprehend the mechanistic details of nanoconjugates versus amoebae as well as their in vivo testing, to develop antimicrobials against the devastating infections caused by these parasites.

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References

  • Abdelnasir S, Anwar A, Kawish M, Anwar A, Shah MR, Siddiqui R, Khan NA (2020) Metronidazole conjugated magnetic nanoparticles loaded with amphotericin B exhibited potent effects against pathogenic Acanthamoeba castellanii belonging to the T4 genotype. AMB Express 10:1–11

    Article  Google Scholar 

  • Agrawal P (2016) Potential prospects of future medicine: nano medicine. J Pharmacovigil 4:1000–1149

    Article  Google Scholar 

  • Akbar N, Gul J, Siddiqui R, Shah MR, Khan NA (2021) Moxifloxacin and sulfamethoxazole-based nanocarriers exhibit potent antibacterial activities. Antibiotics 10:964

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Akbar N, Kawish M, Jabri T, Khan NA, Shah MR, Siddiqui R (2022a) Enhancing efficacy of existing antibacterials against selected multiple drug resistant bacteria using cinnamic acid-coated magnetic iron oxide and mesoporous silica nanoparticles. Pathogen Glob Health 116:438–454

    Article  CAS  Google Scholar 

  • Akbar N, Kawish M, Khan NA, Shah MR, Alharbi AM, Alfahemi H, Siddiqui R (2022b) Hesperidin-, curcumin-, and amphotericin B-based nano-formulations as potential antibacterials. Antibiotics 11:696

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Anwar A, Mungroo MR, Khan S, Fatima I, Rafique R, Kanwal KKM, Siddiqui R, Khan NA (2020) Novel azoles as antiparasitic remedies against brain-eating Amoebae. Antibiotics 9:188

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ashfaque A, Hanif F, Simjee SU, Bari MF, Faizi S, Zehra S, Mirza T, Begum S, Khan L (2021) Opuntiol inhibits growth and induces apoptosis in human glioblastoma cells by upregulating active caspase 3 expression. Asian Pac J Cancer Prev 22(11):3607–3613

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Baig AM (2015) Pathogenesis of amoebic encephalitis: are the amoebae being credited to an ‘inside job’done by the host immune response? Acta Trop 148:72–76

    Article  PubMed  Google Scholar 

  • Bhosale NK, Parija SC (2021) Balamuthia mandrillaris: an opportunistic, free-living ameba—an updated review. Trop Parasitol 11:78

    PubMed  PubMed Central  Google Scholar 

  • Chaubey P, Patel RR, Mishra B (2014) Development and optimization of curcumin-loaded mannosylated chitosan nanoparticles using response surface methodology in the treatment of visceral leishmaniasis. Exp Opin Drug Deliv 11:1163–1181

    Article  CAS  Google Scholar 

  • Cope JR, Landa J, Nethercut H, Collier SA, Glaser C, Moser M, Puttagunta R, Yoder JS, Ali IK, Roy SL (2019) The epidemiology and clinical features of Balamuthia mandrillaris disease in the United States, 1974–2016. Clin Infect Dis 68:1815–1822

    Article  PubMed  Google Scholar 

  • Date AA, Joshi MD, Patravale VB (2007) Parasitic diseases: liposomes and polymeric nanoparticles versus lipid nanoparticles. Adv Drug Deliv Rev 59:505–521

    Article  CAS  PubMed  Google Scholar 

  • Date AA, Nagarsenker MS, Patere S, Dhawan V, Gude RP, Hassan PA, Aswal V, Steiniger F, Thamm J, Fahr A (2011) Lecithin-based novel cationic nanocarriers (Leciplex) II: improving therapeutic efficacy of quercetin on oral administration. Mol Pharmaceut 8:716–726

    Article  CAS  Google Scholar 

  • Debnath A (2021) Drug discovery for primary amebic meningoencephalitis: from screen to identification of leads. Expert Rev Anti Infect Ther 19:1099–1106

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Fan YL, Cheng XW, Wu JB, Liu M, Zhang FZ, Xu Z, Feng L (2018) Antiplasmodial and antimalarial activities of quinolone derivatives: an overview. Eur J Med Chem 146:1–14

    Article  CAS  PubMed  Google Scholar 

  • Gharpure R, Bliton J, Goodman A, Ali IKM, Yoder J, Cope JR (2021) Epidemiology and clinical characteristics of primary amebic meningoencephalitis caused by Naegleria fowleri: a global review. Clin Infect Dis 73:19–27

    Article  Google Scholar 

  • Goy RC, Britto DD, Assis OB (2009) A review of the antimicrobial activity of chitosan. Polímer 19:241–247

    Article  CAS  Google Scholar 

  • Grace E, Asbill S, Virga K (2015) Naegleria fowleri: pathogenesis, diagnosis, and treatment options. Antimicrob Agents Chemother 59:6677–6681

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Haq S, Rehman W, Waseem M, Meynen V, Awan SU, Saeed S, Iqbal N (2018) Fabrication of pure and moxifloxacin functionalized silver oxide nanoparticles for photocatalytic and antimicrobial activity. J Photochem Photobiol B Biol 186:116–124

    Article  CAS  Google Scholar 

  • Hida S, Yoshida M, Nakabayashi I, Miura NN, Adachi Y, Ohno N (2005) Anti-fungal activity of sulfamethoxazole toward Aspergillus species. Biol Pharm Bull 28:773–778

    Article  CAS  PubMed  Google Scholar 

  • International Organization for Standardization, 2009. ISO 10993-5: 2009-Biological evaluation of medical devices-Part 5: Tests for in vitro cytotoxicity. https://nhiso.com/wp-content/uploads/2018/05/ISO-10993-5-2009.pdf

  • Jabri T, Imran M, Rao K, Ali I, Arfan M, Shah MR (2018) Fabrication of lecithin-gum tragacanth muco-adhesive hybrid nano-carrier system for in-vivo performance of Amphotericin B. Carbohyd Polym 194:89–96

    Article  CAS  Google Scholar 

  • Javed I, Hussain SZ, Ullah I, Khan I, Ateeq M, Shahnaz G, ur Rehman H, Razi MT, Shah MR, Hussain I (2015) Synthesis, characterization and evaluation of lecithin-based nanocarriers for the enhanced pharmacological and oral pharmacokinetic profile of amphotericin B. J Mater Chem B 3:8359–8365

    Article  CAS  PubMed  Google Scholar 

  • Javed I, Hussain SZ, Shahzad A, Khan JM, Rehman M, Usman F, Razi MT, Shah MR, Hussain I (2016) Lecithin-gold hybrid nanocarriers as efficient and pH selective vehicles for oral delivery of diacerein—in-vitro and in-vivo study. Colloid Surf B Biointerfaces 141:1–9

    Article  CAS  PubMed  Google Scholar 

  • Jeyamogan S, Khan NA, Anwar A, Shah MR, Siddiqui R (2018) Cytotoxic effects of Benzodioxane, Naphthalene diimide, Porphyrin and Acetamol derivatives on HeLa cells. SAGE Open Medicine 6:2050312118781962

    Article  PubMed  PubMed Central  Google Scholar 

  • Juère E, Florek J, Bouchoucha M, Jambhrunkar S, Wong KY, Popat A, Kleitz F (2017) In vitro dissolution, cellular membrane permeability, and anti-inflammatory response of resveratrol-encapsulated mesoporous silica nanoparticles. Mol Pharmaceut 14:4431–4441

    Article  Google Scholar 

  • Kaasalainen M, Aseyev V, von Haartman E, Karaman DŞ, Mäkilä E, Tenhu H, Rosenholm J, Salonen J (2017) Size, stability, and porosity of mesoporous nanoparticles characterized with light scattering. Nano Res Lett 12:1–10

    Article  CAS  Google Scholar 

  • Katara R, Sachdeva S, Majumdar DK (2019) Design, characterization, and evaluation of aceclofenac-loaded Eudragit RS 100 nanoparticulate system for ocular delivery. Pharm Dev Technol 24:368–379

    Article  CAS  PubMed  Google Scholar 

  • Khan NA, Muhammad JS, Siddiqui R (2021) Brain-eating amoebae: Is killing the parasite our only option to prevent death? Exp Rev Anti Infect Ther:1–2

  • Król-Turmińska K, Olender A (2017) Human infections caused by free-living amoebae. Ann Agric Environ Med 24:254–260

    Article  PubMed  Google Scholar 

  • Kwon S, Singh RK, Perez RA, Abou Neel EA, Kim HW, Chrzanowski W (2013) Silica-based mesoporous nanoparticles for controlled drug delivery. J Tissue Eng 4:2041731413503357

    Article  PubMed  PubMed Central  Google Scholar 

  • Lorenzo-Morales J, Khan NA, Walochnik J (2015) An update on Acanthamoeba keratitis: diagnosis, pathogenesis and treatment. Parasite 22:10

    Article  PubMed  PubMed Central  Google Scholar 

  • Maciver SK, Piñero JE, Lorenzo-Morales J (2020) Is Naegleria fowleri an emerging parasite? Trend Parasitol 36:19–28

    Article  Google Scholar 

  • Manzano M, Aina V, Arean CO, Balas F, Cauda V, Colilla M, Delgado MR, Vallet-Regi M (2008) Studies on MCM-41 mesoporous silica for drug delivery: effect of particle morphology and amine functionalization. Chem Eng J 137:30–37

    Article  CAS  Google Scholar 

  • Matin A, Siddiqui R, Jayasekera S, Khan NA (2008) Increasing importance of Balamuthia mandrillaris. Clin Microbiol Rev 21:435–448

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Minato Y, Dawadi S, Kordus SL, Sivanandam A, Aldrich CC, Baughn AD (2018) Mutual potentiation drives synergy between trimethoprim and sulfamethoxazole. Nat Comm 9:1–7

    Article  CAS  Google Scholar 

  • Mungroo MR, Anwar A, Khan NA, Siddiqui R (2020) Gold-conjugated curcumin as a novel therapeutic agent against brain-eating Amoebae. ACS Omega 5:12467–12475

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Nisar P, Ali N, Rahman L, Ali M, Shinwari ZK (2019) Antimicrobial activities of biologically synthesized metal nanoparticles: an insight into the mechanism of action. J Biol Inorg Chem 24:929–941

    Article  CAS  PubMed  Google Scholar 

  • Ong TYY, Khan NA, Siddiqui R (2017) Brain-eating amoebae: predilection sites in the brain and disease outcome. J Clin Microbiol 55:1989–1997

    Article  PubMed  PubMed Central  Google Scholar 

  • Qadeer A, Ullah H, Sohail M, Safi SZ, Rahim A, Saleh TA, Arbab S, Slama P, Horky P (2022) Potential application of nanotechnology in the treatment, diagnosis, and prevention of schistosomiasis. Front Bioeng Biotechnol 10:1013354

    Article  PubMed  PubMed Central  Google Scholar 

  • Rajendran K, Anwar A, Khan NA, Siddiqui R (2017) Brain-eating Amoebae: silver nanoparticle conjugation enhanced efficacy of anti-amoebic drugs against Naegleria fowleri. ACS Chem Neurosci 8:2626–2630

    Article  CAS  PubMed  Google Scholar 

  • Rice CA, Colon BL, Chen E, Hull MV, Kyle DE (2020) Discovery of repurposing drug candidates for the treatment of diseases caused by pathogenic free-living amoebae. PLoS Negl Trop Dis 14:e0008353

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rocha-Azevedo BD, Jamerson M, Cabral GA, Silva-Filho FC, Marciano-Cabral F (2009) Acanthamoeba interaction with extracellular matrix glycoproteins: biological and biochemical characterization and role in cytotoxicity and invasiveness. J Eukaryot Microbiol 56:270–278

    Article  PubMed  Google Scholar 

  • Roome T, Aziz S, Razzak A, Aslam Z, Jamali KS, Sikandar B, Fatima T, Abidi L, Imran M, Faizi S, Shah MR (2019) Opuntioside, opuntiol and its metallic nanoparticles attenuate adjuvant-induced arthritis: novel suppressors of toll-like receptors-2 and-4. Biomed Pharmacol 112:108624

    Article  CAS  Google Scholar 

  • Saifullah S, Kanwal T, Ullah S, Kawish M, Habib SM, Ali I, Munir A, Imran M, Shah MR (2021) Design and development of lipid modified chitosan containing muco-adhesive self-emulsifying drug delivery systems for cefixime oral delivery. Chem Phys Lipid 235:105052

    Article  CAS  Google Scholar 

  • Saleem R, Ahmad M, Azmat A, Ahmad SI, Faizi Z, Abidi L, Faizi S (2005) Hypotensive activity, toxicology and histopathology of opuntioside-I and methanolic extract of Opuntia dillenii. Biol Pharm Bull 28:1844–1851

    Article  CAS  PubMed  Google Scholar 

  • Schuster FL (2002) Cultivation of pathogenic and opportunistic free-living amebas. Clin Microbiol Rev 15:342–354

    Article  PubMed  PubMed Central  Google Scholar 

  • Sharifi-Rad J, Quispe C, Butnariu M, Rotariu LS, Sytar O, Sestito S, Rapposelli S, Akram M, Iqbal M, Krishna A, Kumar NVA, Braga SS, Cardoso SM, Jafernik K, Ekiert H, Cruz-Martins N, Szopa A, Villagran M, Mardones L, Martorell M, Docea AO, Calina D (2021) Chitosan nanoparticles as a promising tool in nanomedicine with particular emphasis on oncological treatment. Cancer Cell Int 21(1):318

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Siddiqui R, Khamis M, Ibrahim T, Khan NA (2021) Brain-Eating Amoebae in the United Arab Emirates? ACS Pharmacol Transl Sci 4:1014–1015

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Slowing II, Vivero-Escoto JL, Wu CW, Lin VSY (2008) Mesoporous silica nanoparticles as controlled release drug delivery and gene transfection carriers. Adv Drug Del Rev 60:1278–1288

    Article  CAS  Google Scholar 

  • Stewart M, Bartholomew B, Currie F, Abbiw DK, Latif Z, Sarker SD, Nash RJ (2000) Pyranoisoflavones from Rinorea welwitschii. Fitoterapia 71:595–597

    Article  CAS  PubMed  Google Scholar 

  • Taravaud A, Fechtali-Moute Z, Loiseau PM, Pomel S (2021) Drugs used for the treatment of cerebral and disseminated infections caused by free-living amoebae. Clin Transl Sci 14:791–805

    Article  PubMed  PubMed Central  Google Scholar 

  • Trabelsi H, Dendana F, Sellami A, Sellami H, Cheikhrouhou F, Neji S, Makni F, Ayadi A (2012) Pathogenic free-living amoebae: epidemiology and clinical review. Pathol Biol 60:399–405

    Article  CAS  PubMed  Google Scholar 

  • Uri JV, Actor P, Phillips L, Weisbach JA (1978) Semisynthetic cephalosporins with antifungal activity: laboratory studies on 2-pyridinethiol 1-oxide cephalosporins. J Antibiot 31:580–585

    Article  CAS  Google Scholar 

  • Visvesvara GS, Moura H, Schuster FL (2007) Pathogenic and opportunistic free-living amoebae: Acanthamoeba spp., Balamuthia mandrillaris, Naegleria fowleri, and Sappinia diploidea. FEMS Immunol Med Microbiol 50:1–26

    Article  CAS  PubMed  Google Scholar 

  • Zhou Z, Lin S, Yue T, Lee TC (2014) Adsorption of food dyes from aqueous solution by glutaraldehyde cross-linked magnetic chitosan nanoparticles. J Food Eng 126:133–141

    Article  CAS  Google Scholar 

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Funding

This work was funded by University Internal Grant: CSRG 2021/03.

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Authors and Affiliations

  1. College of Arts and Sciences, American University of Sharjah, University City, Sharjah, United Arab Emirates

    Ruqaiyyah Siddiqui & Anania Boghossian

  2. Department of Medical Biology, Faculty of Medicine, Istinye University, Istanbul, 34010, Turkey

    Ruqaiyyah Siddiqui & Naveed Ahmed Khan

  3. College of Medicine, Mohammed Bin Rashid University of Medicine and Health Sciences, 505055, Dubai, United Arab Emirates

    Saif S. Alqassim

  4. International Centre for Chemical and Biological Sciences, H.E.J. Research Institute of Chemistry, University of Karachi, Karachi, 75270, Pakistan

    Muhammad Kawish, Jasra Gul, Tooba Jabri & Muhammad Raza Shah

  5. Department of Clinical Sciences, College of Medicine, University of Sharjah, University City, 27272, Sharjah, United Arab Emirates

    Naveed Ahmed Khan

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  1. Ruqaiyyah Siddiqui
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  2. Anania Boghossian
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  3. Saif S. Alqassim
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  4. Muhammad Kawish
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  8. Naveed Ahmed Khan
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Contributions

RS and NAK conceived the study amid discussion with MRS and SSA. AB carried out experiments related to antimicrobials under the supervision of RS and NAK, while MK, JG, and TJ carried out all experiments related to synthesis, chemistry, and characterization. AB and MK conducted literature search under the supervision of RS, NAK, and MRS. AB and RS prepared the first draft. NAK and MRS corrected the manuscript. All authors approved the final manuscript.

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Correspondence to Naveed Ahmed Khan.

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Communicated by Arivalagan Pugazhendhi.

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Siddiqui, R., Boghossian, A., Alqassim, S.S. et al. Anti-Balamuthia mandrillaris and anti-Naegleria fowleri effects of drugs conjugated with various nanostructures. Arch Microbiol 205, 170 (2023). https://doi.org/10.1007/s00203-023-03518-8

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  • DOI: https://doi.org/10.1007/s00203-023-03518-8

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