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Licensed Unlicensed Requires Authentication Published by De Gruyter June 3, 2016

Nano-mupirocin: enabling the parenteral activity of mupirocin

Ahuva Cern, Ayelet Michael-Gayego, Yaelle Bavli, Erez Koren, Amiram Goldblum, Allon E. Moses, Yan Q. Xiong and Yechezkel Barenholz

Abstract

Mupirocin is an antibiotic having a unique mode of action, not shared by any other therapeutically available antibiotic. However, due to its rapid elimination following injection and high protein binding, current therapeutic use is limited to topical administration. Computational methods have identified mupirocin as a good candidate for delivery via long-circulating nano-liposomes. Formulating mupirocin in such liposomes to form Nano-mupirocin protects the drug in the circulation, enabling therapeutic efficacy. This was demonstrated using two different animal models that served as a proof of concept: the mice necrotizing fasciitis and rabbit endocarditis models. In both animal models, mupirocin administered intravenously (IV) lacked therapeutic efficacy, while the Nano-mupirocin administered IV was efficacious. In both mice and rabbits the pharmacokinetic (PK) profile following IV injection of Nano-mupirocin showed significantly greater AUC and elimination half-life of Nano-mupirocin compared to the free drug. In addition, in mice we also demonstrated significant drug distribution into the disease site. These PK profiles may explain Nano-mupirocin’s superior therapeutic efficacy. To the best of our knowledge, this is the first study demonstrating that systemic activity of mupirocin is feasible. Therefore, Nano-mupirocin can be considered a novel and unique parenteral antibiotic candidate drug.

Acknowledgments

This study was supported by Kamin grant of The Chief Scientist at the Israeli Ministry of Economy and by the Barenholz Fund at the Hebrew University of Jerusalem. This fund originated from royalties Hebrew University received from Yechezkel Barenholz’s commercialized projects. Part of this money is used to support the research activities of the Barenholz Lab. We authors would like to acknowledge Dr. Mary Dan-Goor for her help with the mice study. Mr. Sioma Nudelman and Mrs. Olga Gutman for their help in the preparation of Nano-mupirocin and Mr. Sigmund Geller for editing this paper.

  1. Conflict of interest statement: Y. Barenholz, A. Goldblum and A. Cern are co-inventors on a patent application owned by Yissum, the TTO of the Hebrew University of Jerusalem, that was not yet commercialized.

References

1. Cern A, Golbraikh A, Sedykh A, Tropsha A, Barenholz Y, Goldblum A. Quantitative structure – property relationship modeling of remote liposome loading of drugs. J Control Release 2012;160:147–57.10.1016/j.jconrel.2011.11.029Search in Google Scholar

2. Cern A, Barenholz Y, Tropsha A, Goldblum A. Computer-aided design of liposomal drugs: in silico prediction and experimental validation of drug candidates for liposomal remote loading. J Control Release 2014;173:125–31.10.1016/j.jconrel.2013.10.029Search in Google Scholar

3. Barenholz Y. Liposome application: problems and prospects. Curr Opin Colloid Interface Sci 2001;6:66–77.10.1016/S1359-0294(00)00090-XSearch in Google Scholar

4. Barenholz Y. Relevancy of drug loading to liposomal formulation therapeutic efficacy. J Liposome Res 2003;13:1–8.10.1081/LPR-120017482Search in Google Scholar

5. Zucker D, Marcus D, Barenholz Y, Goldblum A. Liposome drugs’ loading efficiency: a working model based on loading conditions and drug’s physicochemical properties. J Control Release 2009;139:73–80.10.1016/j.jconrel.2009.05.036Search in Google Scholar

6. Advanced Chemistry Development Software V11.02.Search in Google Scholar

7. Cern A, Nativ-Roth E, Goldblum A, Barenholz Y. Effect of solubilizing agents on mupirocin loading into and release from PEGylated nanoliposomes. J Pharm Sci 2014;103:2131–8.10.1002/jps.24037Search in Google Scholar

8. Barenholz Y, Goldblum A, Cern A. Liposomal mupirocin. WO 2015/155773 A1, 2015.Search in Google Scholar

9. Pappa K. The clinical development of mupirocin. J Am Acad Dermatol 1990;22:873–9.10.1016/0190-9622(90)70116-YSearch in Google Scholar

10. Fuller A, Mellows G, Wollford M, Banks G, Barrow K, Chain E. Pseudomonic acid: an antibiotic produced by Pseudomonas fluorescens. Nature 1971;234:416–7.10.1038/234416a0Search in Google Scholar

11. Sutherland R, Boon RJ, Griffin KE, Masters PJ, Slocombe B, White AR. Antibacterial activity of mupirocin (pseudomonic acid), a new antibiotic for topical use. Antimicrob Agents Chemother 1985;27:495–8.10.1128/AAC.27.4.495Search in Google Scholar

12. Hughes J, Mellows G. Interaction of pseudomonic acid A with Escherichia coli B isoleucyl-tRNA synthetase. Biochem J 1980;191:209–19.10.1042/bj1910209Search in Google Scholar

13. GlaxoSmithKline Inc. Product monograph Bactroban.Search in Google Scholar

14. U.S. Department of Health and Human Services Centers for Disease Control and Prevention. Antibiotic resistance threats in the United States, 2013. 2013.Search in Google Scholar

15. Baines P, Jackson D, Mellows G, Swaisland A, Tasker T. Mupirocin: its chemistry and metabolism. In: Wilkinson D, Price J, editors. Mupirocin a novel topical antibiotic. Royal Society of Medicin, London (Distributed by Oxford University Press). International Congress and Symposium Series 80, 1984:13–22.Search in Google Scholar

16. Azzopardi EA, Ferguson EL, Thomas DW. The enhanced permeability retention effect: a new paradigm for drug targeting in infection. J Antimicrob Chemother 2013;68:257–74.10.1093/jac/dks379Search in Google Scholar

17. Barenholz Y. Doxil® – The first FDA-approved nano-drug: lessons learned. J Control Release 2012;160:117–34.10.1016/j.jconrel.2012.03.020Search in Google Scholar

18. Avnir Y, Ulmansky R, Wasserman V, Even-Chen S, Broyer M, Barenholz Y, et al. Amphipathic weak acid glucocorticoid prodrugs remote-loaded into sterically stabilized nanoliposomes evaluated in arthritic rats and in a Beagle dog: a novel approach to treating autoimmune arthritis. Arthritis Rheum 2008;58:119–29.10.1002/art.23230Search in Google Scholar

19. Salem II, Flasher DL, Düzgüneş N. Liposome-encapsulated antibiotics. Methods Enzymol 2005;391:261–91.10.1016/S0076-6879(05)91015-XSearch in Google Scholar

20. http://clinicaltrials.gov. Study to Evaluate Arikace™ in CF Patients With Chronic Pseudomonas Aeruginosa Infections.Search in Google Scholar

21. Schiffelers RM, Storm G, Ten Kate MT, Stearne-Cullen LE, den Hollander JG, Verbrugh HA, et al. In vivo synergistic interaction of liposome-coencapsulated gentamicin and ceftazidime. J Pharmacol Exp Ther 2001;298:369–75.Search in Google Scholar

22. Labana S, Pandey R, Sharma S, Khuller GK. Chemotherapeutic activity against murine tuberculosis of once weekly administered drugs (isoniazid and rifampicin) encapsulated in liposomes. Int J Antimicrob Agents 2002;20:2000–3.10.1016/S0924-8579(02)00175-9Search in Google Scholar

23. Kadry AA, Al-Suwayeh SA, Abd-Allah ARA, Bayomi MA. Treatment of experimental osteomyelitis by liposomal antibiotics. J Antimicrob Chemother 2004;54:1103–8.10.1093/jac/dkh465Search in Google Scholar

24. Wang D, Kong L, Wang J, He X, Li X, Xiao Y. Polymyxin E sulfate-loaded liposome for intravenous use: preparation, lyophilization, and toxicity assessment in vivo. PDA J Pharm Sci Technol 2009;63:159–67.Search in Google Scholar

25. Hidalgo-Grass C, Dan-goor M, Maly A, Eran Y, Kwinn LA, Nizet V, et al. Effect of a bacterial pheromone peptide on host chemokine degradation in group A streptococcal necrotising soft-tissue infections. Mech Dis 2004;363:696–703.10.1016/S0140-6736(04)15643-2Search in Google Scholar

26. Xiong YQ, Kupferwasser LI, Zack PM, Bayer AS. Comparative efficacies of liposomal amikacin (MiKasome) plus oxacillin versus conventional amikacin plus oxacillin in experimental endocarditis induced by Staphylococcus aureus: microbiological and echocardiographic analyses. Antimicrob Agents Chemother 1999;43:1737–42.10.1128/AAC.43.7.1737Search in Google Scholar

27. Abdelhady W, Bayer AS, Seidl K, Moormeier DE, Bayles KW, Cheung A, et al. Impact of vancomycin on sarA-mediated biofilm formation: role in persistent endovascular infections due to methicillin-resistant staphylococcus aureus. J Infect Dis 2014;209:1231–40.10.1093/infdis/jiu007Search in Google Scholar

28. USP 35. Mupirocin official monograph.Search in Google Scholar

29. Druckmann S, Gabizon A, Barenholz Y. Separation of liposome-associated doxorubicin from non-liposome-associated doxorubicin in human plasma: implications for pharmacokinetic studies. Biochim Biophys Acta 1989;980:381–4.10.1016/0005-2736(89)90329-5Search in Google Scholar

30. Amselem S, Gabizon A, Barenholz Y. Optimization and upscaling of doxorubicin-containing liposomes for clinical use. J Pharm Sci 1990;79:1045–52.10.1002/jps.2600791202Search in Google Scholar

31. Avnir Y, Turjeman K, Tulchinsky D, Sigal A, Kizelsztein P, Tzemach D, et al. Fabrication principles and their contribution to the superior in vivo therapeutic efficacy of nano-liposomes remote loaded with glucocorticoids. PLoS One 2011;6:e25721.10.1371/journal.pone.0025721Search in Google Scholar

32. Clerc S, Barenholz Y. Loading of amphipathic weak acids into liposomes in response to transmembrane calcium acetate gradients. Biochim Biophys Acta 1995;1240:257–65.10.1016/0005-2736(95)00214-6Search in Google Scholar

Received: 2016-3-16
Accepted: 2016-4-27
Published Online: 2016-6-3
Published in Print: 2016-7-1

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