Conjugation with Acridines Turns Nuclear Localization Sequence into Highly Active Antimicrobial Peptide

Wei Zhang; Xiaoli Yang; Jingjing Song; Xin Zheng; Jianbo Chen; Panpan Ma; Bangzhi Zhang; Rui Wang

doi:10.15302/J-ENG-2015106

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Engineering ›› 2015, Vol. 1 ›› Issue (4) : 500-505. DOI: 10.15302/J-ENG-2015106

Research

Conjugation with Acridines Turns Nuclear Localization Sequence into Highly Active Antimicrobial Peptide

Wei Zhang¹^,² ,
Xiaoli Yang¹^,² ,
Jingjing Song¹^,² ,
Xin Zheng¹^,² ,
Jianbo Chen¹^,² ,
Panpan Ma¹^,² ,
Bangzhi Zhang¹^,² ,
Rui Wang¹^,²

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Abstract

The emergence of multidrug-resistant bacteria creates an urgent need for alternative antibiotics with new mechanisms of action. In this study, we synthesized a novel type of antimicrobial agent, Acr₃-NLS, by conjugating hydrophobic acridines to the N-terminus of a nuclear localization sequence (NLS), a short cationic peptide. To further improve the antimicrobial activity of our agent, dimeric (Acr₃-NLS)₂ was simultaneously synthesized by joining two monomeric Acr₃-NLS together via a disulfide linker. Our results show that Acr₃-NLS and especially (Acr₃-NLS)₂ display significant antimicrobial activity against gram-negative and gram-positive bacteria compared to that of the NLS. Subsequently, the results derived from the study on the mechanism of action demonstrate that Acr₃-NLS and (Acr₃-NLS)₂ can kill bacteria by membrane disruption and DNA binding. The double targets–cell membrane and intracellular DNA–will reduce the risk of bacteria developing resistance to Acr₃-NLS and (Acr₃-NLS)₂. Overall, this study provides a novel strategy to design highly effective antimicrobial agents with a dual mode of action for infection treatment.

Keywords

acridine / nuclear localization sequence / conjugate / antimicrobial activity / mechanism of action

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Wei Zhang, Xiaoli Yang, Jingjing Song, Xin Zheng, Jianbo Chen, Panpan Ma, Bangzhi Zhang, Rui Wang. Conjugation with Acridines Turns Nuclear Localization Sequence into Highly Active Antimicrobial Peptide. Engineering, 2015, 1(4): 500‒505 https://doi.org/10.15302/J-ENG-2015106

References

Publishing order | Descend order by publishing year | Descend order by cited within

[1]	M. S. Butler, M. A. Blaskovich, M. A. Cooper. Antibiotics in the clinical pipeline in 2013. J. Antibiot., 2013, 66(10): 571–591

[2]	C. W. Pouton, K. M. Wagstaff, D. M. Roth, G. W. Moseley, D. A. Jans. Targeted delivery to the nucleus. Adv. Drug Deliv. Rev., 2007, 59(8): 698–717

[3]	L. J. Brandén, A. J. Mohamed, C. I. Smith. A peptide nucleic acid-nuclear localization signal fusion that mediates nuclear transport of DNA. Nat. Biotechnol., 1999, 17(8): 784–787

[4]	T. Shiraishi, R. Hamzavi, P. E. Nielsen. Targeted delivery of plasmid DNA into the nucleus of cells via nuclear localization signal peptide conjugated to DNA intercalating bis- and trisacridines. Bioconjug. Chem., 2005, 16(5): 1112–1116

[5]	N. Kobayashi, Y. Yamada, T. Yoshida. Nuclear translocation peptides as antibiotics. Antimicrob. Agents Chemother., 2006, 50(3): 1118–1119

[6]	J. Feigon, W. A. Denny, W. Leupin, D. R. Kearns. Interactions of antitumor drugs with natural DNA: ¹H NMR study of binding mode and kinetics. J. Med. Chem., 1984, 27(4): 450–465

[7]	R. Kumar, M. Kaur, M. Kumari. Acridine: A versatile heterocyclic nucleus. Acta Pol. Pharm., 2012, 69(1): 3–9

[8]	G. Cholewiński, K. Dzierzbicka, A. M. Kołodziejczyk. Natural and synthetic acridines/acridones as antitumor agents: Their biological activities and methods of synthesis. Pharmacol. Rep., 2011, 63(2): 305–336

[9]	A. F. Valdés. Acridine and acridinones: Old and new structures with antimalarial activity. Open Med. Chem. J., 2011, 5: 11–20

[10]	M. Wainwright. Acridine—A neglected antibacterial chromophore. J. Antimicrob. Chemother., 2001, 47(1): 1–13

[11]	S. Majumdar, T. J. Siahaan. Peptide-mediated targeted drug delivery. Med. Res. Rev., 2012, 32(3): 637–658

[12]	V. M. Ahrens, K. Bellmann-Sickert, A. G. Beck-Sickinger. Peptides and peptide conjugates: Therapeutics on the upward path. Future Med. Chem., 2012, 4(12): 1567–1586

[13]	A. Pini, Antimicrobial activity of novel dendrimeric peptides obtained by phage display selection and rational modification. Antimicrob. Agents Chemother., 2005, 49(7): 2665–2672

[14]	E. N. Lorenzón, Effects of dimerization on the structure and biological activity of antimicrobial peptide Ctx-Ha. Antimicrob. Agents Chemother., 2012, 56(6): 3004–3010

[15]	J. Wang, S. Li, T. Luo, C. Wang, J. Zhao. Disulfide linkage: A potent strategy in tumor-targeting drug discovery. Curr. Med. Chem., 2012, 19(18): 2976–2983

[16]	N. J. Baumhover, K. Anderson, C. A. Fernandez, K. G. Rice. Synthesis and in vitro testing of new potent polyacridine-melittin gene delivery peptides. Bioconjug. Chem., 2010, 21(1): 74–83

[17]	J. Song, Design of an acid-activated antimicrobial peptide for tumor therapy. Mol. Pharm., 2013, 10(8): 2934–2941

[18]	M. Zasloff. Antimicrobial peptides of multicellular organisms. Nature, 2002, 415(6870): 389–395

[19]	M. R. Yeaman, N. Y. Yount. Mechanisms of antimicrobial peptide action and resistance. Pharmacol. Rev., 2003, 55(1): 27–55

[20]	A. Schmidtchen, M. Pasupuleti, M. Malmsten. Effect of hydrophobic modifications in antimicrobial peptides. Adv. Colloid. Interfac., 2014, 205: 265–274

[21]	Z. Jiang, A. I. Vasil, J. D. Hale, R. E. W. Hancock, M. L. Vasil, R. S. Hodges. Effects of net charge and the number of positively charged residues on the biological activity of amphipathic α-helical cationic antimicrobial peptides. Biopolymers, 2008, 90(3): 369–383

[22]	L. M. Yin, M. A. Edwards, J. Li, C. M. Yip, C. M. Deber. Roles of hydrophobicity and charge distribution of cationic antimicrobial peptides in peptide-membrane interactions. J. Biol. Chem., 2012, 287(10): 7738–7745

[23]	N. Sitaram, R. Nagaraj. Interaction of antimicrobial peptides with biological and model membranes: Structural and charge requirements for activity. Biochim. Biophys. Acta, 1999, 1462(1−2): 29–54

[24]	Y. Chen, M. T. Guarnieri, A. I. Vasil, M. L. Vasil, C. T. Mant, R. S. Hodges. Role of peptide hydrophobicity in the mechanism of action of α-helical antimicrobial peptides. Antimicrob. Agents Chemother., 2007, 51(4): 1398–1406

[25]	T. Tachi, R. F. Epand, R. M. Epand, K. Matsuzaki. Position-dependent hydrophobicity of the antimicrobial magainin peptide affects the mode of peptide-lipid interactions and selective toxicity. Biochemistry, 2002, 41(34): 10723–10731

[26]	J. Song, Cell penetrating peptide TAT can kill cancer cells via membrane disruption after attachment of camptothecin. Peptides, 2015, 63: 143–149

[27]	L. H. Kondejewski, Dissociation of antimicrobial and hemolytic activities in cyclic peptide diastereomers by systematic alterations in amphipathicity. J. Biol. Chem., 1999, 274(19): 13181–13192

[28]	C. E. Dempsey, S. Ueno, M. B. Avison. Enhanced membrane permeabilization and antibacterial activity of a disulfide-dimerized magainin analogue. Biochemistry, 2003, 42(2): 402–409

[29]	K. A. Brogden. Antimicrobial peptides: Pore formers or metabolic inhibitors in bacteria? Nat. Rev. Microbiol., 2005, 3(3): 238–250

[30]	P. Nicolas. Multifunctional host defense peptides: Intracellular-targeting antimicrobial peptides. FEBS J., 2009, 276(22): 6483–6496

[31]	J. Yan, Two hits are better than one: Membrane-active and DNA binding-related double-action mechanism of NK-18, a novel antimicrobial peptide derived from mammalian NK-lysin. Antimicrob. Agents Chemother., 2013, 57(1): 220–228

[32]	S. T. Henriques, M. N. Melo, M. A. R. B. Castanho. Cell-penetrating peptides and antimicrobial peptides: How different are they? Biochem. J., 2006, 399(1): 1–7

Acknowledgements

We are grateful for the grants from the National Natural Science Foundation of China (81402776 and 81202400), the Key National S&T Program “Major New Drug Development” of the Ministry of Science and Technology of China (2012ZX09504-001-003), the Fundamental Research Funds for the Central Universities (lzujbky-2014-142 and lzujbky-2015-169), the Specialized Research Fund for the Doctoral Program of Higher Education of China (20130211130005), and China Postdoctoral Science Foundation (2013T60896).

Compliance with ethics guidelines

Wei Zhang, Xiaoli Yang, Jingjing Song, Xin Zheng, Jianbo Chen, Panpan Ma, Bangzhi Zhang, and Rui Wang declare that they have no conflict of interest or financial conflicts to disclose.