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The AAPS Journal

, Volume 15, Issue 1, pp 132–142 | Cite as

Amino-Terminated Generation 2 Poly(amidoamine) Dendrimer as a Potential Broad-Spectrum, Nonresistance-Inducing Antibacterial Agent

  • Xiaoyan Xue
  • Xiaoqing Chen
  • Xinggang Mao
  • Zheng Hou
  • Ying Zhou
  • Hui Bai
  • Jingru Meng
  • Fei Da
  • Guojun Sang
  • Yukun Wang
  • Xiaoxing Luo
Research Article

Abstract

The treatment of septicemia caused by antibiotic-resistant bacteria is a great challenge in the clinic. Because traditional antibiotics inevitably induce bacterial resistance, which is responsible for many treatment failures, there is an urgent need to develop novel antibiotic drugs. Amino-terminated Poly(amidoamine) dendrimers (PAMAM-NH2) are reported to have antibacterial activities. However, previous studies focused on high generations of PAMAM-NH2, which have been found to exhibit high toxicities. The present study aimed to clarify whether low generations of PAMAM-NH2 could be used as novel antibacterial agents. We found that generation 2 (G2.0) PAMAM-NH2 showed significant antibacterial effects against antibiotic-sensitive and antibiotic-resistant strains but exhibited little toxicity to human gastric epithelial cells and did not induce antibiotic resistance in bacteria. Scanning and transmission electron microscopy analyses suggested that G2.0 PAMAM-NH2 might inhibit the growth of bacteria by destroying their cell membranes. The administration of G2.0 PAMAM-NH2 dose-dependently improved the animal survival rate of mice infected with extended-spectrum beta lactamase-producing Escherichia coli (ESBL-EC) and of animals infected with a combination of ESBL-EC and methicillin-resistant Staphylococcus aureus. A treatment regimen of 10 mg/kg of G2.0 PAMAM-NH2 starting 12 h before inoculation followed by 10 mg/kg at 0.5 h after inoculation rescued 100% of singly infected mice and 60% of multiply infected mice. The protective effects were associated with the reduction of the bacterial titers in the blood and with the morphological amelioration of infected tissues. These findings demonstrate that the G2.0 PAMAM-NH2 is a potential broad-spectrum and nonresistance-inducing antibiotic agent with relatively low toxicity.

Key words

antibacterial activity antibiotic resistance extended-spectrum beta lactamase-producing Escherichia coli methicillin-resistant Staphylococcus aureus PAMAM dendrimers 

Notes

Acknowledgments

This research was supported by grants from the National Fund for Natural Science, China (No. 30973666). The authors would like to thank Prof. Liping Zhao (Shang Hai Jiao Tong University, Shanghai, China) for the bacterial strain E. coli MG1655 and Na Chai, Ph.D., (Xijing Affiliated Hospital, Fourth Military Medical University, Xi’an, China) for the endothelial cell line.

Disclosure Statement

The authors declare that they have no conflicts of interest to disclose.

Ethical approval

The animal experiments were approved by the Ethics Committee of the Fourth Military Medical University.

Supplementary material

12248_2012_9416_MOESM1_ESM.docx (5.1 mb)
ESM 1 (DOCX 5198 kb)

References

  1. 1.
    Gyssens IC. Antibiotic policy. Int J Antimicrob Agents. 2011;38(Suppl):11–20.PubMedCrossRefGoogle Scholar
  2. 2.
    Jean SS, Hsueh PR. High burden of antimicrobial resistance in Asia. Int J Antimicrob Agents. 2011;37:291–5.PubMedCrossRefGoogle Scholar
  3. 3.
    Wang JL, Wang JT, Chen SY, Chen YC, Chang SC. Distribution of staphylococcal cassette chromosome mec types and correlation with comorbidity and infection type in patients with MRSA bacteremia. PLoS One. 2010;5:e9489.PubMedCrossRefGoogle Scholar
  4. 4.
    Fischbach MA, Walsh CT. Antibiotics for emerging pathogens. Science. 2009;325:1089–93.PubMedCrossRefGoogle Scholar
  5. 5.
    Castonguay A, Ladd E, van de Ven TGM, Kakkar A. Dendrimers as bactericides. New J Chem. 2012;36:199–204.CrossRefGoogle Scholar
  6. 6.
    Mintzer MA, Dane EL, O’Toole GA, Grinstaff MW. Exploiting dendrimer multivalency to combat emerging and re-emerging infectious diseases. Mol Pharm. 2012;9:342–54.PubMedCrossRefGoogle Scholar
  7. 7.
    Han L, Huang R, Li J, Liu S, Huang S, Jiang C. Plasmid pORF-hTRAIL and doxorubicin co-delivery targeting to tumor using peptide-conjugated polyamidoamine dendrimer. Biomaterials. 2011;32:1242–52.PubMedCrossRefGoogle Scholar
  8. 8.
    Beg S, Samad A, Alam MI, Nazish I. Dendrimers as novel systems for delivery of neuropharmaceuticals to the brain. CNS Neurol Disord Drug Targets. 2011;10:576–88.PubMedCrossRefGoogle Scholar
  9. 9.
    Gajbhiye V, Palanirajan VK, Tekade RK, Jain NK. Dendrimers as therapeutic agents: a systematic review. J Pharm Pharmacol. 2009;61:989–1003.PubMedCrossRefGoogle Scholar
  10. 10.
    Nanjwade BK, Bechra HM, Derkar GK, Manvi FV, Nanjwade VK. Dendrimers: emerging polymers for drug-delivery systems. Eur J Pharm Sci. 2009;38:185–96.PubMedCrossRefGoogle Scholar
  11. 11.
    Lopez AI, Reins RY, McDermott AM, Trautner BW, Cai C. Antibacterial activity and cytotoxicity of PEGylated poly(amidoamine) dendrimers. Mol Biosyst. 2009;5:1148–56.PubMedCrossRefGoogle Scholar
  12. 12.
    Calabretta MK, Kumar A, McDermott AM, Cai C. Antibacterial activities of poly(amidoamine) dendrimers terminated with amino and poly(ethylene glycol) groups. Biomacromolecules. 2007;8:1807–11.PubMedCrossRefGoogle Scholar
  13. 13.
    Roberts JC, Bhalgat MK, Zera RT. Preliminary biological evaluation of polyamidoamine (PAMAM) Starburst dendrimers. J Biomed Mater Res. 1996;30:53–65.PubMedCrossRefGoogle Scholar
  14. 14.
    Malik N, Wiwattanapatapee R, Klopsch R, Lorenz K, Frey H, Weener JW, et al. Dendrimers: relationship between structure and biocompatibility in vitro, and preliminary studies on the biodistribution of 125I-labelled polyamidoamine dendrimers in vivo. J Control Release. 2000;65:133–48.PubMedCrossRefGoogle Scholar
  15. 15.
    McNerny DQ, Leroueil PR, Baker JR. Understanding specific and nonspecific toxicities: a requirement for the development of dendrimer-based pharmaceuticals. Wiley Interdiscip Rev Nanomed Nanobiotechnol. 2010;2:249–59.PubMedCrossRefGoogle Scholar
  16. 16.
    Ortega P, Copa-Patino JL, Munoz-Fernandez MA, Soliveri J, Gomez R, de la Mata FJ. Amine and ammonium functionalization of chloromethylsilane-ended dendrimers. Antimicrobial activity studies. Org Biomol Chem. 2008;6:3264–9.PubMedCrossRefGoogle Scholar
  17. 17.
    Eichler M, Katzur V, Scheideler L, Haupt M, Geis-Gerstorfer J, Schmalz G, et al. The impact of dendrimer-grafted modifications to model silicon surfaces on protein adsorption and bacterial adhesion. Biomaterials. 2011;32:9168–79.PubMedCrossRefGoogle Scholar
  18. 18.
    Wang L, Erasquin UJ, Zhao M, Ren L, Zhang MY, Cheng GJ, et al. Stability, antimicrobial activity, and cytotoxicity of poly(amidoamine) dendrimers on titanium substrates. ACS Appl Mater Interfaces. 2011;3:2885–94.PubMedCrossRefGoogle Scholar
  19. 19.
    Wang B, Navath RS, Menjoge AR, Balakrishnan B, Bellair R, Dai H, et al. Inhibition of bacterial growth and intramniotic infection in a guinea pig model of chorioamnionitis using PAMAM dendrimers. Int J Pharm. 2010;395:298–308.PubMedCrossRefGoogle Scholar
  20. 20.
    Cheng Y, Qu H, Ma M, Xu Z, Xu P, Fang Y, et al. Polyamidoamine (PAMAM) dendrimers as biocompatible carriers of quinolone antimicrobials: an in vitro study. Eur J Med Chem. 2007;42:1032–8.PubMedCrossRefGoogle Scholar
  21. 21.
    Ghosh S, Ghosh D, Bag PK, Bhattacharya SC, Saha A. Aqueous synthesis of ZnTe/dendrimer nanocomposites and their antimicrobial activity: implications in therapeutics. Nanoscale. 2011;3:1139–48.PubMedCrossRefGoogle Scholar
  22. 22.
    Neelgund GM, Oki A. Deposition of silver nanoparticles on dendrimer functionalized multiwalled carbon nanotubes: synthesis, characterization and antimicrobial activity. J Nanosci Nanotechnol. 2011;11:3621–9.PubMedCrossRefGoogle Scholar
  23. 23.
    Reynolds R, Shackcloth J, Felmingham D, MacGowan A. Comparison of BSAC agar dilution and NCCLS broth microdilution MIC methods for in vitro susceptibility testing of Streptococcus pneumoniae, Haemophilus influenzae and Moraxella catarrhalis: the BSAC Respiratory Resistance Surveillance Programme. J Antimicrob Chemother. 2003;52:925–30.PubMedCrossRefGoogle Scholar
  24. 24.
    Kumar A, Yellepeddi VK, Vangara KK, Strychar KB, Palakurthi S. Mechanism of gene transfection by polyamidoamine (PAMAM) dendrimers modified with ornithine residues. J Drug Target. 2011;19:770–80.PubMedCrossRefGoogle Scholar
  25. 25.
    Xue XY, Zhou Y, Chen YY, Meng JR, Jia M, Hou Z, et al. Promoting effects of chemical permeation enhancers on insulin permeation across TR146 cell model of buccal epithelium in vitro. Drug Chem Toxicol. 2011;35 :199–207.PubMedCrossRefGoogle Scholar
  26. 26.
    Gilles HJ. Calculation of the index of acute toxicity by the method of linear regression. Comparison with the method of “Karber and Behrens”. Eur J Toxicol Environ Hyg. 1974;7:77–84.PubMedGoogle Scholar
  27. 27.
    Ulrich R, Miller J. Threshold estimation in two-alternative forced-choice (2AFC) tasks: the Spearman–Karber method. Percept Psychophys. 2004;66:517–33.PubMedCrossRefGoogle Scholar
  28. 28.
    Radzishevsky IS, Rotem S, Bourdetsky D, Navon-Venezia S, Carmeli Y, Mor A. Improved antimicrobial peptides based on acyl-lysine oligomers. Nat Biotechnol. 2007;25:657–9.PubMedCrossRefGoogle Scholar
  29. 29.
    Rozgonyi F, Szabo D, Kocsis B, Ostorhazi E, Abbadessa G, Cassone M, et al. The antibacterial effect of a proline-rich antibacterial peptide A3-APO. Curr Med Chem. 2009;16:3996–4002.PubMedCrossRefGoogle Scholar
  30. 30.
    Sadekar S, Ghandehari H. Transepithelial transport and toxicity of PAMAM dendrimers: implications for oral drug delivery. Adv Drug Deliv Rev. 2011;64:571–88.PubMedCrossRefGoogle Scholar
  31. 31.
    Cao W, Zhou J, Mann A, Wang Y, Zhu L. Folate-functionalized unimolecular micelles based on a degradable amphiphilic dendrimer-like star polymer for cancer cell-targeted drug delivery. Biomacromolecules. 2011;12:2697–707.PubMedCrossRefGoogle Scholar
  32. 32.
    Samad A, Alam MI, Saxena K. Dendrimers: a class of polymers in the nanotechnology for the delivery of active pharmaceuticals. Curr Pharm Des. 2009;15:2958–69.PubMedCrossRefGoogle Scholar

Copyright information

© American Association of Pharmaceutical Scientists 2012

Authors and Affiliations

  • Xiaoyan Xue
    • 1
  • Xiaoqing Chen
    • 1
  • Xinggang Mao
    • 2
  • Zheng Hou
    • 1
  • Ying Zhou
    • 1
  • Hui Bai
    • 1
  • Jingru Meng
    • 1
  • Fei Da
    • 1
  • Guojun Sang
    • 1
  • Yukun Wang
    • 1
  • Xiaoxing Luo
    • 1
  1. 1.Department of Pharmacology, School of PharmacyThe Fourth Military Medical UniversityXi’anPeople’s Republic of China
  2. 2.Department of Neurosurgery, Xijing HospitalThe Fourth Military Medical UniversityXi’anPeople’s Republic of China

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