Skip to main content
Log in

In Vitro Inhibitory Effects and Bioinformatic Analysis of Norfloxacin and Ofloxacin on Piroplasm

  • Original Paper
  • Published:
Acta Parasitologica Aims and scope Submit manuscript

Abstract

Purpose

The in vitro inhibitory effect of two fluroquinolone antibiotics, norfloxacin and ofloxacin, was evaluated in this study on the growth of several Babesia and Theileria parasites with highlighting the bioinformatic analysis for both drugs with the commonly used antibabesial drug, diminazene aceturate (DA), and the recently identified antibabesial drugs, luteolin, and pyronaridine tetraphosphate (PYR).

Methods

The antipiroplasm efficacy of screened fluroquinolones in vitro and in vivo was assessed using a fluorescence-based SYBR Green I assay. Using atom Pair signatures, we investigated the structural similarity between fluroquinolones and the antibabesial drugs.

Results

Both fluroquinolones significantly inhibited (P < 0.05) the in vitro growths of Babesia bovis (B. bovis), B. bigemina, B. caballi, and Theileria equi (T. equi) in a dose-dependent manner. The best inhibitory effect for both drugs was observed on the growth of T. equi. Atom Pair fingerprints (APfp) results and AP Tanimoto values revealed that both fluroquinolones, norfloxacin with luteolin, and ofloxacin with PYR, showed the maximum structural similarity (MSS). Two drug interactions findings confirmed the synergetic interaction between these combination therapies against the in vitro growth of B. bovis and T. equi.

Conclusion

This study helped in discovery novel potent antibabesial combination therapies consist of norfloxacin/ofloxacin, norfloxacin/luteolin, and ofloxacin/PYR.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

Data Availability

The datasets generated during and/or analyzed during the current study are available from the corresponding authors on reasonable request.

References

  1. Suarez CE, Alzan HF, Silva MG, Rathinasamy V, Poole WA, Cooke BM (2019) Unravelling the cellular and molecular pathogenesis of bovine babesiosis: is the sky the limit? Int J Parasitol 49(2):183–197. https://doi.org/10.1016/j.ijpara.2018.11.002

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Rizk MA, El-Sayed SAE, Nassif M, Mosqueda J, Xuan X, Igarashi I (2020) Assay methods for in vitro and in vivo anti-Babesia drug efficacy testing: current progress, outlook, and challenges. Vet Parasitol 279:109013. https://doi.org/10.1016/j.vetpar.2019.109013

    Article  CAS  PubMed  Google Scholar 

  3. Mosqueda J, Olvera-Ramirez A, Aguilar-Tipacamu G, Canto GJ (2012) Current advances in detection and treatment of babesiosis. Curr Med Chem 19(10):1504–1518. https://doi.org/10.2174/092986712799828355

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Rizk MA, El-Sayed SAE, Eltaysh R, Igarashi I (2022) MMV020275 and MMV020490, promising compounds from malaria box for the treatment of equine piroplasmosis. Ticks Tick Borne Dis 13(2):101904. https://doi.org/10.1016/j.ttbdis.2022.101904

    Article  PubMed  Google Scholar 

  5. Rizk MA, Baghdadi HB, El-Sayed SAE, Eltaysh R, Igarashi I (2022) Repurposing of the malaria box for Babesia microti in mice identifies novel active scaffolds against piroplasmosis. Parasit Vectors 15(1):329. https://doi.org/10.1186/s13071-022-05430-4

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Rizk MA, El-Sayed SAE, El-Khodery S, Yokoyama N, Igarashi I (2019) Discovering the in vitro potent inhibitors against Babesia and Theileria parasites by repurposing the malaria box: a review. Vet Parasitol 274:108895. https://doi.org/10.1016/j.vetpar.2019.07.003

    Article  CAS  PubMed  Google Scholar 

  7. Rizk MA, AbouLaila M, El-Sayed SAE, Guswanto A, Yokoyama N, Igarashi I (2018) Inhibitory effects of fluoroquinolone antibiotics on Babesia divergens and Babesia microti, blood parasites of veterinary and zoonotic importance. Infect Drug Resist 11:1605–1615. https://doi.org/10.2147/IDR.S159519

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Blondeau JM, Borsos S, Blondeau LD, Blondeau BJ (2012) In vitro killing of Escherichia coli, staphylococcus pseudintermedius and pseudomonas aeruginosa by enrofloxacin in combination with its active metabolite ciprofloxacin using clinically relevant drug concentrations in the dog and cat. Vet Microbiol 155(2–4):284–290. https://doi.org/10.1016/j.vetmic.2011.08.015

    Article  CAS  PubMed  Google Scholar 

  9. Dalhoff A (2015) Antiviral, antifungal, and antiparasitic activities of fluoroquinolones optimized for treatment of bacterial infections: a puzzling paradox or a logical consequence of their mode of action? Eur J Clin Microbiol Infect Dis 34(4):661–668. https://doi.org/10.1007/s10096-014-2296-3

    Article  CAS  PubMed  Google Scholar 

  10. El-Sayed SAE, Rizk MA, Ringo AE, Li Y, Liu M, Ji S, Li J, Byamukama B, Tumwebaze MA, Xuan X, Igarashi I (2021) Impact of using pyronaridine tetraphosphate- based combination therapy in the treatment of babesiosis caused by Babesia bovis, B. caballi, and B. gibsoni in vitro and B. microti in mice. Parasitol Int 81:102260. https://doi.org/10.1016/j.parint.2020.102260

    Article  CAS  PubMed  Google Scholar 

  11. El-Sayed SAE, Rizk MA, Yokoyama N, Igarashi I (2019) Evaluation of the in vitro and in vivo inhibitory effect of thymoquinone on piroplasm parasites. Parasit Vectors 12(1):37. https://doi.org/10.1186/s13071-019-3296-z

    Article  PubMed  PubMed Central  Google Scholar 

  12. Rizk MA, El-Sayed SAE, AbouLaila M, Yokoyama N, Igarashi I (2017) Evaluation of the inhibitory effect of N-acetyl-L-cysteine on Babesia and Theileria parasites. Exp Parasitol 179:43–48. https://doi.org/10.1016/j.exppara.2017.06.003

    Article  CAS  PubMed  Google Scholar 

  13. Rizk MA, El-Sayed SAE, Igarashi I (2021) Evaluation of the inhibitory effect of Zingiber officinale rhizome on Babesia and Theileria parasites. Parasitol Int 85:102431. https://doi.org/10.1016/j.parint.2021.102431

    Article  CAS  PubMed  Google Scholar 

  14. Rizk MA, El-Sayed SA, AbouLaila M, Tuvshintulga B, Yokoyama N, Igarashi I (2016) Large-scale drug screening against Babesia divergens parasite using a fluorescence-based high-throughput screening assay. Vet Parasitol 227:93–97. https://doi.org/10.1016/j.vetpar.2016.07.032

    Article  CAS  PubMed  Google Scholar 

  15. Rizk MA, El-Sayed SA, Terkawi MA, Youssef MA, Said El, el Sel S, Elsayed G, El-Khodery S, El-Ashker M, Elsify A, Omar M, Salama A, Yokoyama N, Igarashi I (2015) Optimization of a fluorescence-based assay for large-scale drug screening against Babesia and Theileria parasites. PLoS ONE 10(4):e0125276. https://doi.org/10.1371/journal.pone.0125276

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. O’Boyle NM, Sayle RA (2016) Comparing structural fingerprints using a literature based similarity benchmark. J Cheminform 8:2206–2219

    Article  Google Scholar 

  17. Rizk MA, El-Sayed SAE, Alkhoudary MS, Alsharif KF, Abdel-Daim MM, Igarashi I (2021) Compounds from the medicines for malaria venture box inhibit in vitro growth of Babesia divergens, a blood-borne parasite of veterinary and zoonotic importance. Molecules 26(23):7118. https://doi.org/10.3390/molecules26237118

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Backman TW, Cao Y, Girke T (2011) ChemMine tools: an online service for analyzing and clustering small molecules. Nucleic Acids Res 39:W486-491. https://doi.org/10.1093/nar/gkr320

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Cao Y, Charisi A, Cheng LC, Jiang T, Girke T (2008) ChemmineR: a compound mining framework for R. Bioinformatics 24:1733–1744

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Smythe MA, Rybak MJ (1989) Ofloxacin: a review. DICP 23(11):839–846. https://doi.org/10.1177/106002808902301101

    Article  CAS  PubMed  Google Scholar 

  21. Mahmoudi N, Ciceron L, Franetich JF, Farhati K, Silvie O, Eling W, Sauerwein R, Danis M, Mazier D, Derouin F (2003) In vitro activities of 25 quinolones and fluoroquinolones against liver and blood stage Plasmodium spp. Antimicrob Agents Chemother 47(8):2636–2639. https://doi.org/10.1128/AAC.47.8.2636-2639.2003

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Drlica K (1999) Mechanism of fluoroquinolone action. Curr Opin Microbiol 2(5):504–508. https://doi.org/10.1016/s1369-5274(99)00008-9

    Article  CAS  PubMed  Google Scholar 

  23. McFadden GI, Roos DS (1999) Apicomplexan plastids as drug targets. Trends Microbiol 7(8):328–333. https://doi.org/10.1016/s0966-842x(99)01547-4

    Article  CAS  PubMed  Google Scholar 

  24. Garcia-Estrada C, Prada CF, Fernandez-Rubio C, Rojo-Vazquez F, Balana-Fouce R (2010) DNA topoisomerases in apicomplexan parasites: promising targets for drug discovery. Proc Biol Sci 277(1689):1777–1787. https://doi.org/10.1098/rspb.2009.2176

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Bender A, Glen RC (2004) Molecular similarity: a key technique in molecular informatics. Org Biomol Chem 2(22):3204–3218. https://doi.org/10.1039/B409813G

    Article  CAS  PubMed  Google Scholar 

  26. Eckert H, Bajorath J (2007) Molecular similarity analysis in virtual screening: foundations, limitations and novel approaches. Drug Discov Today 12(5–6):225–233. https://doi.org/10.1016/j.drudis.2007.01.011

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors would like to thank Prof. Naoaki Yokoyama, National Research Center for Protozoan Diseases, Obihiro University of Agriculture and Veterinary Medicine, Inada-Cho, Obihiro, Hokkaido, Japan, for his scientific support and discussion.

Funding

This study was supported by the Ministry of Education, Culture, Sports, Science and Technology of Japan. Mohamed Abdo Rizk was supported by a research grant fellowship for young scientists from the Japan Society for the Promotion of Science (JSPS) (ID no. P18091).

Author information

Authors and Affiliations

Authors

Contributions

MAR and II contributed to conceptualization, investigation, and resources. MAR and SAESES contributed to data curation and formal analysis, software, writing – original draft, and methodolog. II contributed to funding acquisition, project administration, and supervision. SAESES and II contributed to validation. All authors contributed to visualization and writing – review & editing.

Corresponding authors

Correspondence to Mohamed Abdo Rizk, Shimaa Abd El-Salam El-Sayed or Ikuo Igarashi.

Ethics declarations

Conflict of Interest

The authors declare that they have no competing interests.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (DOCX 20 KB)

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Rizk, M.A., El-Sayed, S.A.ES. & Igarashi, I. In Vitro Inhibitory Effects and Bioinformatic Analysis of Norfloxacin and Ofloxacin on Piroplasm. Acta Parasit. 68, 213–222 (2023). https://doi.org/10.1007/s11686-022-00648-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11686-022-00648-9

Keywords

Navigation