Poly(styrene-alt-maleic anhydride) Conjugated with Spermine: Synthesis, Antibacterial Activity and Antibiotic Susceptibility

Document Type : Research Paper

Authors

Ferdowsi University of Mashhad, Mashhad, Postal code: 9177948974, Iran

Abstract

Hypothesis: In the past decades, the increasing resistance to antibiotics among some nosocomial infection pathogens has been one of the largest challenges of human health. One of the ways to reduce antibiotic resistance in bacteria is the combination use of cationic polymers with antibiotics. Poly(styrene-alt-maleic-anhydride) (PSMA) is an alternative biodegradable copolymer which can react with bioactive agents such as alkyl amines through a ring-opening reaction. In this study, for the first time, the antibacterial activity of poly(styrene-alt-maleic-anhydride) (PSMA) conjugated with spermine (Spm-PSMA) and its influence on resistance of Enterococcus faecalis to ceftazidime and ciprofloxacin antibiotics have been investigated.
Methods: Spm-PSMA was synthesized by reaction of PSMA with spermine in the presence of triethylamine catalyst under argon atmosphere at room temperature and characterized by FTIR and DSC. The antibacterial activity of Spm-PSMA was evaluated against two nosocomial infective bacteria, Enterococcus faecalis (E. faecalis) and Acinetobacter baumannii (A. baumannii) by two-fold microdilution method. Its ability to reduce the resistance of E. faecalis to the ciprofloxacin (CP) and ceftazidime (CAZ) antibiotics, active oxygen species (ROS) levels and morphological changes in acidic conditions was evaluated.
Findings: The glass transition temperature of Spm-PSMA (197°C) is higher than that of PSMA (164°C) due to intermolecular hydrogen bonding. Spm-PSMA reduces the growth of Gram-positive E. faecalis in a dose-independent manner, whereas it has no significant antibacterial activity against Gram-negative A. baumannii in acidic condition. E. faecalis susceptibility to ceftazidime and ciprofloxacin antibiotics is increased in the presence of Spm-PSMA at pH 5.5. The SEM results show that Spm-PSMA alone and in combination with antibiotics causes the transformation of E. faecalis cells from coccoid to coccobacilli shape. The results of this study show that Spm-PSMA is a biocompatible polymer with antibacterial activity and antibiotic sensitivity against E. faecalis bacteria.

Keywords


  1. Peleg A.Y., Seifert H., and Paterson, D.L., Acinetobacter Baumannii: Emergence of a Successful P athogen, Clin.Microbiol. Rev., 21, 538-582, 2008.
  2. Bassetti M., Ginocchio F., and Mikulska M., New Treatment Options Against Gram-Negative Organisms, Crit. Care, 15, 1, 2011.
  3. Dong C., Ye Y., Qian L., Zhao G., He B., and Xiao H., Antibacterial Modification of Cellulose Fibers by Grafting β-Cyclodextrin and Inclusion with Ciprofloxacin, Cellulose, 21, 1921-1932, 2014.
  4. Majumdar P., He J., Lee E., Kallam A., Gubbins N., Stafslien S.J., Daniels J., and Chisholm B.J., Antimicrobial Activity of Polysiloxane Coatings Containing Quaternary Ammonium-Functionalized Polyhedral Oligomeric Silsesquioxane, J. Coat.Technol. Res., 7, 455-467, 2010.
  5. Xue Y., Xiao H., and Zhang Y., Antimicrobial Polymeric Materials with Quaternary Ammonium and Phosphonium Salts, Int. J. Mol. Sci., 16, 3626-3655, 2015.
  6. LeeY.S. and Byoun Y.S., Poly(styrene-co-4-vinylbenzyl chloride) Conjugated with 3-(dimethylamino) Phenol: Synthesis and Antibacterial Activity, Bull. Korean Chem. Soc., 23, 1833-1835, 2002.
  7. Kenawy E.R., Worley S.D., and Broughton R., The Chemistry and Applications of Antimicrobial Polymers: A State-of-the-Art Review, Biomacromolecules, 8, 1359-1384, 2007.
  8. Sovadinova I., Palermo E.F., Urban M., Mpiga P., Caputo G.A., and Kuroda K., Activity and Mechanism of Antimicrobial Peptide-Mimetic Amphiphilic Polymethacrylate Derivatives, Polymers, 3, 1512−1532, 2011.
  9. Zasloff M., Antimicrobial Peptides of Multicellular Organisms, Nature, 415, 389-395, 2002.
  10. Baghersad S., Mansurnezhad R., Ghasemi Mobarakeh L., Mola Hosseini H., and Morshed M., Coating of Silk Fabrics by PVA/Ciprofloxacin HCl Nanofibers for Biomedical Applications, Iran. J. Polym. Sci. Technol. (Persian), 29, 171-184, 2016.
  11. Elvira C., Gallardo A., Roman J., and Cifuentes A., Covalent Polymer-Drug Conjugates, Molecules, 10, 114-125, 2005.
  12. Csákvári É., Azori M., and Tüdös F., Physico-chemical Studies of Polymeric Carriers, Polym. Bull., 12, 553-556, 1984.
  13. Venditti I., Morphologies and Functionalities of Polymeric Nanocarriers as Chemical Tools for Drug Delivery: A Review, J.  King Saud University-Science, In Press, 2017.
  14. Katti D.S., Lakshmi S., Langer R., and Laurencin C.T., Toxicity, Biodegradation and Elimination of Polyanhydrides, Adv. Drug Deliv. Rev., 54, 933-961, 2002.
  15. Larson N., Greish K., Bauer H., Maeda H., and Ghandehari H., Synthesis and Evaluation of Poly(styrene-co-maleic acid) Micellar Nanocarriers for the Delivery of Tanespimycin, Int. J. Pharm., 420, 111−117, 2011.
  16. Johnson D., New Applications for Poly(ethylene-alt-maleic anhydride), PhD Thesis, Durham University, 2010.
  17. Oda T. and Maeda H., Binding to and Internalization by Cultured Cells of Neocarzinostatin and Enhancement of Its Actions by Conjugation with Lipophilic Styrene-Maleic Acid Copolymer, Cancer Res., 47, 3206-3211, 1987.
  18. Henry S.M., El-Sayed M.E., Pirie C.M., Hoffman A.S., and Stayton P.S., pH-responsive Poly(styrene-alt-maleic anhydride) Alkylamide Copolymers for Intracellular Drug Delivery. Biomacromolecules, 7, 2407-2414, 2006.
  19. Duncan R., Ringsdorf H., and Satchi-Fainaro R., Polymer Therapeutics-Polymers as Drugs, Drug and Protein Conjugates and Gene Delivery Systems: Past, Present and Future Opportunities, J. Drug Target, 14, 337-341, 2006.
  20. Mu Y., Kamada H., Kaneda Y., Yamamoto Y., Kodaira H., Tsunoda S.I., Tsutsumi Y., Maeda M., Kawasaki K., Nomizu M., and Yamada Y., Bioconjugation of Laminin Peptide YIGSR with Poly(styrene-co-maleic acid) Increases Its Antimetastatic Effect on Lung Metastasis of B16-BL6 Melanoma Cells, Biochem. Biophys. Res. Commun., 255, 75-79, 1999.
  21. Greish K., Sawa T., Fang J., Akaike T., and Maeda H., SMA-doxorubicin, a New Polymeric Micellar Drug for Effective Targeting to Solid Tumours, J. Control. Rel., 97, 219-230, 2003.
  22. Alex M.A., Nagpal N., Kulshreshtha R., and Koul V., Synthesis and Evaluation of Cationically Modified Poly(styrene-alt-maleic anhydride) Nanocarriers for Intracellular Gene Delivery, RSC Adv., 5, 21931-21944, 2015.
  23. Jackman J.G., Juwarker H., Poveromo L.P., Levinson H., Leong K.W., and Sullenger B.A., Polycationic Nanofibers for Nucleic Acid Scavenging, Biomacromolecules, 17, 3706-3713, 2016.
  24. Winek C.L. and Burgun J.J., Acute and Subacute Toxicology and Safety Evaluation of SMA 1440-H Resin, Clin.Toxicol., 10, 255-260, 1977.
  25. Fang W., Cai Y., Chen X., Su R., Chen T., Xia N., Li L., Yang Q., Han J., and Han S., Poly(styrene-alt-maleic anhydride) Derivatives as Potent Anti-HIV Microbicide Candidates, Bioorg. Med. Chem. Lett., 19, 1903-1907, 2009.
  26. Singh H., Jabbal M.S., Ray A.R., and Vasudevan P., Effect of Anionic Polymeric Hydrogels on Spermatozoa Motility, Biomaterials, 5, 307-309, 1984.
  27. Jeong J.H., Byoun Y.S., and Lee Y.S., Poly(styrene-alt-maleic anhydride)-4-Aminophenol Conjugate: Synthesis and Antibacterial Activity, React. Funct. Polym., 50, 257-263, 2002.
  28. Dewangan R.P., Joshi S., Kumari S., Gautam H., Yar M.S., and Pasha S., N-Terminally Modified Linear and Branched Spermine Backbone Dipeptidomimetics Against Planktonic and Sessile Methicillin-Resistant Staphylococcus aureus, Antimicrob. Agents Chemother., 58, 5435-5447, 2014.
  29. Grossowicz N., Razin S., and Rozansky R., Factors Influencing the Antibacterial Action of Spermine And Spermidine on Staphylococcus aureus, Microbiology, 13, 436-441, 1955.
  30. Kwon D.H. and Lu C.D., Polyamines Increase Antibiotic Susceptibility in Pseudomonas aeruginosa, Antimicrob. Agents Chemother., 50, 1623-1627, 2006.
  31. Kwon D.H. and Lu C.D., Polyamine Effects on Antibiotic Susceptibility in Bacteria, Antimicrob. Agents Chemother., 51, 2070−2077, 2007.
  32. Khalil H., Chen T., Riffon R., Wang R., and Wang Z., Synergy Between Polyethylenimine and Different Families of Antibiotics Against a Resistant Clinical Isolate of Pseudomonas aeruginosaAntimicrob. Agents Chemother., 52, 1635-1641, 2008.
  33. Jeong J. H., Byoun Y.S., Ko S.B., and Lee Y.S., Chemical Modification of Poly(styrene-alt-maleic anhydride) with Antimicrobial 4-Aminobenzoic Acid and 4-Hydroxybenzoic Acid, J. Ind. Eng. Chem., 7, 310–315, 2001.
  34. Rajput S.R., Rupainwar D.C., and Singh A., A Study on Styrene maleic Anhydride Modification by Benzoic acid Derivatives and Dimethyl Sulfoxide, Int. J. Chemtech. Res., 1, 915–919, 2009.
  35. Barawkar D.A., Rajeev K.G., Kumar V.A., and Ganesh K.N., Triplex Formation at Physiological pH by 5-Me-dC-N4-(spermine) [X] oligodeoxynucleotides: Non Protonation of N3 in X of X* G: C Triad and Effect of Base Mismatch/Ionic Strength on Triplex Stabilities, Nucleic Acids Res., 24, 1229−1237, 1996.
  36. Bachrach U. and Weinstein A., Effect of Aliphatic Polyamines on Growth and Macromolecular Syntheses in Bacteria, Microbiology, 60, 159−165, 1970.
  37. Yao X. and Lu C.D., Characterization of Staphylococcus aureusresponses to Spermine Stress, Curr. Microbiol., 69, 394-403, 2014.
  38. Mills J. and Dubin D.T., Some Effects of Spermine on Escherichia coli, Mol. Pharmacol., 2, 311−318, 1966.
  39. Marzabadi M.R. and Lovaas E., Spermine Prevent Iron Accumulation and Depress Lipofuscin Accumulation in Cultured Myocardial Cells, Free Radic. Biol. Med., 21, 375−381, 1996.
  40. Haley K.P. and Skaar E.P., A Battle for Iron: Host Sequestration and Staphylococcus aureus Acquisition, Microb. Infect., 14, 217−227, 2012.
  41. Joshi G.S., Spontak J.S., Klapper D.G., and Richardson A.R., Arginine Catabolic Mobile Element Encoded speG Abrogates the Unique Hypersensitivity of Staphylococcus aureus to Exogenous Polyamines, Mol. Microbiol., 82, 9−20, 2011.
  42. Fair W.R. and Wehner N., Antibacterial Action of Spermine: Effect on Urinary Tract Pathogens, Appl. Microbiol., 21, 6−8, 1971.
  43. Wiley J.M., Sherwood L.M., and Woolverton, C.J., Prescott’s Microbiology, McGraw Hill Education, USA, 42-82, 2013.
  44. Malanovic N. and Lohner K., Gram-positive Bacterial Cell Envelopes: The Impact on the Activity of Antimicrobial Peptides, Biochim. Biophys. Acta Biomembr., 1858, 936–946, 2016.
  45. Ha H.C., Sirisoma N.S., Kuppusamy P., Zweier J.L., Woster P.M., and Casero R.A., The Natural Polyamine Spermine Functions Directly as a Free Radical Scavenger, Proc. Natl. Acad. Sci. USA95, 11140−11145, 1998.
  46. Justice S.S., Hunstad D.A., Cegelski L., and Hultgren S.J., Morphological Plasticity as a Bacterial Survival Strategy, Nat. Rev. Microbiol.,6, 162–168, 2008.