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Pharmacokinetics, tissue distribution, bioavailability and excretion of the anti-virulence drug Fluorothiazinon in rats and rabbits

The Journal of Antibiotics volume 77, pages 382–388 (2024)Cite this article

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Abstract

Growing antimicrobial resistance has accelerated the development of anti-virulence drugs to suppress bacterial toxicity without affecting cell viability. Fluorothiazinon (FT), an anti-virulence, type three secretion system and flagella motility inhibitor which has shown promise to suppress drug-resistant pathogens having the potential to enhance the efficacy of commonly prescribed antibiotics when used in combination. In this study we characterized the pharmacokinetics, tissue distribution, bioavailability and excretion of FT in rats and rabbits. FT presented a dose-proportional linear increase in the blood of rats. Tissue distribution profiling confirmed that FT distributes to all organs being substantially higher than in the blood of rats. The bioavailability of FT was higher when administered with starch than with water implying FT should be ideally dosed with food. FT was primarily excreted in the feces in rats and rabbits while negligible amounts are recovered from the urine.

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References

  1. Naylor NR, et al. Quantifying the primary and secondary effects of antimicrobial resistance on surgery patients: Methods and data sources for empirical estimation in England. Front Public Health. 2022;10:803943.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Anesi JA, et al. Impact of donor multidrug-resistant organisms on solid organ transplant recipient outcomes. Transpl Infect Dis J Transpl Soc. 2022;24:e13783.

    Article  Google Scholar 

  3. Akash MSH, Rehman K, Fiayyaz F, Sabir S, Khurshid M. Diabetes-associated infections: development of antimicrobial resistance and possible treatment strategies. Arch Microbiol. 2020;202:953–65.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Nanayakkara AK, et al. Antibiotic resistance in the patient with cancer: Escalating challenges and paths forward. CA Cancer J Clin. 2021;71:488–504.

    Article  PubMed  Google Scholar 

  5. Wang Y, Luo Q, Xiao T, Zhu Y, Xiao Y. Impact of Polymyxin Resistance on Virulence and Fitness among Clinically Important Gram-Negative Bacteria. Engineering. 2022;13:178–85.

    Article  Google Scholar 

  6. Righi E, et al. ESCMID/EUCIC clinical practice guidelines on perioperative antibiotic prophylaxis in patients colonized by multidrug-resistant Gram-negative bacteria before surgery. Clin Microbiol Infect. 2023;29:463–79.

    Article  CAS  PubMed  Google Scholar 

  7. Mühlen S, Dersch P. Anti-virulence Strategies to Target Bacterial Infections. In: Stadler M, Dersch P, editors. How to Overcome the Antibiotic Crisis. Cham: Springer International Publishing; 2015. p. 147–83.

  8. Lee B, Boucher HW. Targeting antimicrobial-resistant bacterial respiratory tract pathogens: it is time to “get smart.”. Curr Opin Pulm Med. 2015;21:293–303.

    Article  CAS  PubMed  Google Scholar 

  9. Rasko DA, Sperandio V. Anti-virulence strategies to combat bacteria-mediated disease. Nat Rev Drug Discov. 2010;9:117–28.

    Article  CAS  PubMed  Google Scholar 

  10. Uusitalo P, et al. The salicylidene acylhydrazide INP0341 attenuates Pseudomonas aeruginosa virulence in vitro and in vivo. J Antibiot. 2017;70:937–43.

    Article  CAS  Google Scholar 

  11. Fasciano AC, Shaban L, Mecsas J. Promises and Challenges of the Type Three Secretion System Injectisome as an Antivirulence Target. In: Sandkvist M, Cascales E, Christie PJ, editors. EcoSal Plus. 2019;8:ecosalplus.ESP-0032-2018.

  12. Lyons BJE, Strynadka NCJ. On the road to structure-based development of anti-virulence therapeutics targeting the type III secretion system injectisome. MedChemComm. 2019;10:1273–89.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. François B, et al. New Strategies Targeting Virulence Factors of Staphylococcus aureus and Pseudomonas aeruginosa. Semin Respir Crit Care Med. 2017;38:346–58.

    Article  PubMed  Google Scholar 

  14. Czaplewski L, et al. Alternatives to antibiotics—a pipeline portfolio review. Lancet Infect Dis. 2016;16:239–51.

    Article  CAS  PubMed  Google Scholar 

  15. Yap CH, Tay ST, Chee CF. Indole Derivative (UM-3E) as an Antimicrobial and Antivirulence Strategy for the Prevention of Staphylococcus aureus Biofilm-associated Infections. Int J Infect Dis. 2023;130:S115–6.

    Article  Google Scholar 

  16. Rezzoagli C, Archetti M, Mignot I, Baumgartner M, Kümmerli R. Combining antibiotics with antivirulence compounds can have synergistic effects and reverse selection for antibiotic resistance in Pseudomonas aeruginosa. Schulenburg H, editor. PLOS Biol. 2020;18:e3000805.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Bondareva NE, et al. Preventative treatment with Fluorothiazinon suppressed Acinetobacter baumannii-associated septicemia in mice. J Antibiot. 2022;75:155–63.

    Article  CAS  Google Scholar 

  18. Koroleva EA, et al. Fluorothiazinon inhibits the virulence factors of uropathogenic Escherichia coli involved in the development of urinary tract infection. J Antibiot. 2023;76:279–90.

    Article  CAS  Google Scholar 

  19. Tsarenko SV, et al. A novel antivirulent compound fluorothiazinone inhibits Klebsiella pneumoniae biofilm in vitro and suppresses model pneumonia. J Antibiot. 2023;76:397–405.

    Article  CAS  Google Scholar 

  20. Savitskii MV, et al. Pharmacokinetics, quorum-sensing signal molecules and tryptophan-related metabolomics of the novel anti-virulence drug Fluorothiazinon in a Pseudomonas aeruginosa-induced pneumonia murine model. J Pharm Biomed Anal. 2023;236:115739.

    Article  CAS  PubMed  Google Scholar 

  21. Moskaleva NE, Baranov PA, Mesonzhnik NV, Appolonova SA. HPLC–MS/MS method for the simultaneous quantification of desmethylmebeverine acid, mebeverine acid and mebeverine alcohol in human plasma along with its application to a pharmacokinetics study. J Pharm Biomed Anal. 2017;138:118–25.

    Article  CAS  PubMed  Google Scholar 

  22. Sheng Y, et al. Systematic Evaluation of Dose Proportionality Studies in Clinical Pharmacokinetics. Curr Drug Metab. 2010;11:526–37.

    Article  CAS  PubMed  Google Scholar 

  23. Hummel J, McKendrick S, Brindley C, French R. Exploratory assessment of dose proportionality: review of current approaches and proposal for a practical criterion. Pharm Stat. 2009;8:38–49.

    Article  PubMed  Google Scholar 

  24. Jager NGL, Van Hest RM, Lipman J, Roberts JA, Cotta MO. Antibiotic exposure at the site of infection: principles and assessment of tissue penetration. Expert Rev Clin Pharmacol. 2019;12:623–34.

    Article  CAS  PubMed  Google Scholar 

  25. Liu P, Müller M, Derendorf H. Rational dosing of antibiotics: the use of plasma concentrations versus tissue concentrations. Int J Antimicrob Agents. 2002;19:285–90.

    Article  CAS  PubMed  Google Scholar 

  26. Zigangirova NA, et al. Fluorothiazinon, a small-molecular inhibitor of T3SS, suppresses salmonella oral infection in mice. J Antibiot. 2021;74:244–54.

    Article  CAS  Google Scholar 

  27. Koziolek M, et al. The mechanisms of pharmacokinetic food-drug interactions – A perspective from the UNGAP group. Eur J Pharm Sci. 2019;134:31–59.

    Article  CAS  PubMed  Google Scholar 

  28. Roberts MS, Magnusson BM, Burczynski FJ, Weiss M. Enterohepatic Circulation: Physiological, Pharmacokinetic and Clinical Implications. Clin Pharmacokinet. 2002;41:751–90.

    Article  CAS  PubMed  Google Scholar 

  29. Wagenlehner FME, Weidner W, Naber KG. Pharmacokinetic Characteristics of Antimicrobials and Optimal Treatment of Urosepsis. Clin Pharmacokinet. 2007;46:291–305.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This research was funded by the Ministry of Science and Higher Education of the Russian Federation within the framework of state support for the creation and development of World-Class Research Centers “Digital Biodesign and Personalized Healthcare”, grant number 075-15-2022-304.

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Authors and Affiliations

  1. Laboratory of Pharmacokinetics and Metabolomic Analysis, Institute of Translational Medicine and Biotechnology, Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russian Federation

    Mark V. Savitskii, Natalia E. Moskaleva, Alex Brito, Pavel A. Markin, Franco Tagliaro & Svetlana A. Appolonova

  2. Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russian Federation

    Mark V. Savitskii, Vadim V. Tarasov, Kristina A. Tatzhikova & Svetlana A. Appolonova

  3. Unit of Forensic Medicine, Department of Diagnostics and Public Health, University of Verona, Verona, Italy

    Mark V. Savitskii & Franco Tagliaro

  4. World Class Research Center Digital Biodesign and Personalized Healthcare, Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russian Federation

    Natalia E. Moskaleva

  5. National Research Center for Epidemiology and Microbiology named after N. F. Gamaleya, Russian Health Ministry, Moscow, Russian Federation

    Nailya A. Zigangirova, Anna V. Soloveva, Anna B. Sheremet, Natalia E. Bondareva & Nadezhda L. Lubenec

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  1. Mark V. Savitskii
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Correspondence to Natalia E. Moskaleva.

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Savitskii, M.V., Moskaleva, N.E., Brito, A. et al. Pharmacokinetics, tissue distribution, bioavailability and excretion of the anti-virulence drug Fluorothiazinon in rats and rabbits. J Antibiot 77, 382–388 (2024). https://doi.org/10.1038/s41429-024-00719-1

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