Nitroxoline Evidence Amoebicidal Activity Against Acanthamoeba Castellanii Through DNA Damage and the Stress Response Pathways

Overview

Journal Int J Parasitol Drugs Drug Resist

Publisher Elsevier

Specialty Parasitology

Date 2025 Jan 7

PMID 39764873

Authors

Lijun Chen

Wei Han

Wenwen Jing

Meng Feng

Qingtong Zhou

Xunjia Cheng

Affiliations

Soon will be listed here.

Abstract

Acanthamoeba castellanii is a widespread unicellular eukaryote found in diverse environments, including tap water, soil, and swimming pools. It is responsible for severe infections, such as Acanthamoeba keratitis and granulomatous amebic encephalitis, particularly in individuals with immunocompromisation. The ability of protozoans to form dormant and persistent cysts complicates treatment, as current therapies are ineffective against cyst stages and suffer from poor specificity and side effects. Nitroxoline, a quinoline derivative with well-established antibacterial, antifungal, and antiviral properties, is a promising therapeutic candidate. This study aimed to elucidate cellular signalling events that counteract the effects of nitroxoline. In this study, nitroxoline significantly reduced the viability of A. castellanii trophozoites in a dose- and time-dependent manner, inducing morphological changes and apoptosis. Transcriptomic analysis revealed substantial alterations in gene expression, including enrichment of metabolic pathways, DNA damage responses, and iron ion binding. Nitroxoline treatment upregulated genes involved in DNA repair and oxidative stress response while regulating genes in the methionine and cysteine cycles. It also decreased the mitochondrial membrane potential, H₂S production, and total iron amount in A. castellanii. Bioinformatic analyses and molecular docking studies suggest direct interactions between nitroxoline and several A. castellanii proteins. Our research provides a comprehensive molecular map of the response of A. castellanii to nitroxoline, revealing significant changes in gene expression related to the stress response and metabolic pathways. These findings underscore the potential of nitroxoline as a potent anti-Acanthamoeba agent, offering new insights into its mechanism of action and paving the way for effective combinational therapeutic strategies.

References

Damhorst G, Watts A, Hernandez-Romieu A, Mel N, Palmore M, Ali I . Acanthamoeba castellanii encephalitis in a patient with AIDS: a case report and literature review. Lancet Infect Dis. 2021; 22(2):e59-e65. PMC: 10910629. DOI: 10.1016/S1473-3099(20)30933-6. View

Zhu J, Berisa M, Schworer S, Qin W, Cross J, Thompson C . Transsulfuration Activity Can Support Cell Growth upon Extracellular Cysteine Limitation. Cell Metab. 2019; 30(5):865-876.e5. PMC: 6961654. DOI: 10.1016/j.cmet.2019.09.009. View

Wang M, Liang X, Cheng M, Yang L, Liu H, Wang X . Homocysteine enhances neural stem cell autophagy in in vivo and in vitro model of ischemic stroke. Cell Death Dis. 2019; 10(8):561. PMC: 6646339. DOI: 10.1038/s41419-019-1798-4. View

Zhang Y, Xu X, Wei Z, Cao K, Zhang Z, Liang Q . The global epidemiology and clinical diagnosis of Acanthamoeba keratitis. J Infect Public Health. 2023; 16(6):841-852. DOI: 10.1016/j.jiph.2023.03.020. View

Joaquim A, Gionbelli M, Gosmann G, Fuentefria A, Lopes M, de Andrade S . Novel Antimicrobial 8-Hydroxyquinoline-Based Agents: Current Development, Structure-Activity Relationships, and Perspectives. J Med Chem. 2021; 64(22):16349-16379. DOI: 10.1021/acs.jmedchem.1c01318. View

Ogrady F, Smith B . Neuromyopathy in the mouse produced by the antimicrobial agent nitroxoline. J Pathol Bacteriol. 1966; 92(1):43-8. DOI: 10.1002/path.1700920106. View

Tain L, Jain C, Nespital T, Froehlich J, Hinze Y, Gronke S . Longevity in response to lowered insulin signaling requires glycine N-methyltransferase-dependent spermidine production. Aging Cell. 2019; 19(1):e13043. PMC: 6974722. DOI: 10.1111/acel.13043. View

Haston J, Cope J . Amebic encephalitis and meningoencephalitis: an update on epidemiology, diagnostic methods, and treatment. Curr Opin Infect Dis. 2023; 36(3):186-191. PMC: 10798061. DOI: 10.1097/QCO.0000000000000923. View

Hirukawa Y, Nakato H, Izumi S, Tsuruhara T, Tomino S . Structure and expression of a cyst specific protein of Acanthamoeba castellanii. Biochim Biophys Acta. 1998; 1398(1):47-56. DOI: 10.1016/s0167-4781(98)00026-8. View

10.

Aoyagi Y, Hayashi Y, Harada Y, Choi K, Matsunuma N, Sadato D . Mitochondrial Fragmentation Triggers Ineffective Hematopoiesis in Myelodysplastic Syndromes. Cancer Discov. 2021; 12(1):250-269. DOI: 10.1158/2159-8290.CD-21-0032. View

11.

Fuchs F, Becerra-Aparicio F, Xanthopoulou K, Seifert H, Higgins P . In vitro activity of nitroxoline against carbapenem-resistant Acinetobacter baumannii isolated from the urinary tract. J Antimicrob Chemother. 2022; 77(7):1912-1915. DOI: 10.1093/jac/dkac123. View

12.

Ouyang Y, Wu Q, Li J, Sun S, Sun S . S-adenosylmethionine: A metabolite critical to the regulation of autophagy. Cell Prolif. 2020; 53(11):e12891. PMC: 7653241. DOI: 10.1111/cpr.12891. View

13.

Deschner F, Risch T, Baier C, Schluter D, Herrmann J, Muller R . Nitroxoline resistance is associated with significant fitness loss and diminishes virulence of . Microbiol Spectr. 2023; 12(1):e0307923. PMC: 10782962. DOI: 10.1128/spectrum.03079-23. View

14.

. UniProt: the Universal Protein Knowledgebase in 2023. Nucleic Acids Res. 2022; 51(D1):D523-D531. PMC: 9825514. DOI: 10.1093/nar/gkac1052. View

15.

Lampe R, Coale T, Forsch K, Jabre L, Kekuewa S, Bertrand E . Short-term acidification promotes diverse iron acquisition and conservation mechanisms in upwelling-associated phytoplankton. Nat Commun. 2023; 14(1):7215. PMC: 10632500. DOI: 10.1038/s41467-023-42949-1. View

16.

Huang J, Ko P, Huang C, Wen P, Chen C, Shih M . Cytochrome P450 monooxygenase of Acanthamoeba castellanii participates in resistance to polyhexamethylene biguanide treatment. Parasite. 2021; 28:77. PMC: 8582484. DOI: 10.1051/parasite/2021074. View

17.

Liu Z, Tang W, Liu J, Han Y, Yan Q, Dong Y . A novel sprayable thermosensitive hydrogel coupled with zinc modified metformin promotes the healing of skin wound. Bioact Mater. 2022; 20:610-626. PMC: 9256661. DOI: 10.1016/j.bioactmat.2022.06.008. View

18.

Salazar O, N Arun P, Cui G, Bay L, van Oppen M, Webster N . The coral genome reveals an alternative pathway for cysteine biosynthesis in animals. Sci Adv. 2022; 8(38):eabq0304. PMC: 9506716. DOI: 10.1126/sciadv.abq0304. View

19.

Paulet L, Trecourt A, Leary A, Peron J, Descotes F, Devouassoux-Shisheboran M . Cracking the homologous recombination deficiency code: how to identify responders to PARP inhibitors. Eur J Cancer. 2022; 166:87-99. DOI: 10.1016/j.ejca.2022.01.037. View

20.

Friesner R, Murphy R, Repasky M, Frye L, Greenwood J, Halgren T . Extra precision glide: docking and scoring incorporating a model of hydrophobic enclosure for protein-ligand complexes. J Med Chem. 2006; 49(21):6177-96. DOI: 10.1021/jm051256o. View