Jump to ContentJump to Main Navigation
Show Summary Details
More options …

Pure and Applied Chemistry

The Scientific Journal of IUPAC

Ed. by Burrows, Hugh / Stohner, Jürgen

IMPACT FACTOR 2017: 5.294

CiteScore 2017: 3.42

SCImago Journal Rank (SJR) 2017: 1.212
Source Normalized Impact per Paper (SNIP) 2017: 1.546

See all formats and pricing
More options …
Volume 91, Issue 2


Combating bacterial resistance by combination of antibiotics with antimicrobial peptides

Dean E. Sheard / Neil M. O’Brien-Simpson
  • Centre of Oral Health Research, Melbourne Dental School, University of Melbourne, Melbourne, VIC 3010, Australia
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
/ John D. Wade
  • School of Chemistry, Bio21 Institute, University of Melbourne, Melbourne, VIC 3010, Australia
  • The Florey Institute of Neuroscience and Mental Health, University of Melbourne, Melbourne, VIC 3010, Australia
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
/ Frances SeparovicORCID iD: https://orcid.org/0000-0002-6484-2763
Published Online: 2019-01-29 | DOI: https://doi.org/10.1515/pac-2018-0707


The overuse of antibiotics in the healthcare and agricultural industries has led to the worldwide spread of bacterial resistance. The recent emergence of multidrug resistant (MDR) bacteria has resulted in a call for the development of novel strategies to address this global issue. Research on a diverse range of antimicrobial peptides (AMPs) has shown promising activity against several resistant strains. Increased understanding of the mode of action of AMPs has shown similarity and complementarity to conventional antibiotics and the combination of both has led to synergistic effects in some cases. Combination therapy has been widely used to combat MDR bacterial infections and the recent focus on their application with AMPs may allow antibiotics to be effective against resistant bacterial strains. By conjugation of an antibiotic onto an AMP, a compound may be produced with possibly greater activity and with reduced side-effects and toxicity. The AMP in these conjugates may also act as a unique adjuvant for the antibiotic by disrupting the resistance mechanisms used by bacteria thus allowing the antibiotic to once again be effective. This mini-review outlines some of the current and past work in combining AMPs with conventional antibiotics as strategies to address bacterial resistance.

Keywords: antibiotics; antimicrobial activity; Distinguished Women in Chemistry and Chemical Engineering; membranes; peptides


  • [1]

    BBC – Future – How We Can Stop Antibiotic Resistance. http://www.bbc.com/future/story/20170607-how-we-can-stop-antibiotic-resistance (accessed Jul 5 2018).

  • [2]

    Antimicrobial Resistance: Global Report on Surveillance, World Health Organization (WHO), Geneva, Switzerland (2014).Google Scholar

  • [3]

    E. Zankari, H. Hasman, S. Cosentino, M. Vestergaard, S. Rasmussen, O. Lund, F. M. Aarestrup, M. V. Larsen. J. Antimicrob. Chemother. 67, 2640 (2012).CrossrefGoogle Scholar

  • [4]

    M.-D. Seo, H.-S. Won, J.-H. Kim, T. Mishig-Ochir, B. J. Lee. Molecules 17, 12276 (2012).CrossrefGoogle Scholar

  • [5]

    B. Mishra, S. Reiling, D. Zarena, G. Wang. Curr. Opin. Chem. Biol. 38, 87 (2017).CrossrefGoogle Scholar

  • [6]

    J. D. Spencer, A. L. Schwaderer, B. Becknell, J. Watson, D. S. Hains. Pediatr. Nephrol. 29, 1139 (2014).CrossrefGoogle Scholar

  • [7]

    L.-J. Zhang, R. Gallo. Curr. Biol. 26, R14 (2016).CrossrefGoogle Scholar

  • [8]

    G. Wang. Pharmaceuticals 7, 545 (2014).CrossrefGoogle Scholar

  • [9]

    K. Brogden. Nat. Rev. Microbiol. 3, 238 (2005).CrossrefGoogle Scholar

  • [10]

    J. Renukuntla, A. Vadlapudi, A. Patel, S. H. Boddu, A. K. Mitra. Int. J. Pharm. 447, 75 (2013).CrossrefGoogle Scholar

  • [11]

    N. Brogden, K. A. Brogden. Int. J. Antimicrob. Agents 38, 217 (2011).Google Scholar

  • [12]

    S. Dosler, E. Mataraci. Peptides 49, 53 (2013).CrossrefGoogle Scholar

  • [13]

    C. Rüter, C. Buss, J. Scharnert, G. Heusipp, M. A. Schmidt. J. Cell Sci. 123, 2190 (2010).CrossrefGoogle Scholar

  • [14]

    R. E. Hancock, D. S. Chapple. Antimicrob. Agents Chemother. 43, 1317 (1999).CrossrefGoogle Scholar

  • [15]

    R. E. W. Hancock, R. Hancock. Lancet Infect. Dis. 5, 209 (2005).CrossrefGoogle Scholar

  • [16]

    L. Nguyen, E. Haney, H. Vogel. Trends Biotechnol. (Regular ed.) 29, 464 (2011).Google Scholar

  • [17]

    J. M. Leveritt Iii, J. Leveritt, A. Pino Angeles. Biophys. J. 108, 2424 (2015).CrossrefGoogle Scholar

  • [18]

    D. Fernandez, M.-A. Sani, F. Separovic. Aust. J. Chem. 64, 798 (2011).CrossrefGoogle Scholar

  • [19]

    E. Jamasbi, S. Batinovic, R. A. Sharples, M. A. Sani, R. M. Robins-Browne, J. D. Wade, F. Separovic, M. A. Hossain. Amino Acids 46, 2759 (2014).CrossrefGoogle Scholar

  • [20]

    L. Otvos, J. D. Wade, F. Lin, B. A. Condie, J. Hanrieder, R. Hoffmann. J. Med. Chem. 48, 5349 (2005).CrossrefGoogle Scholar

  • [21]

    S. Blondelle, R. Houghten. Biochemistry 31, 12688 (1992).CrossrefGoogle Scholar

  • [22]

    Y. Sang, F. Blecha. Anim. Health Res. Rev. 9, 227 (2008).CrossrefGoogle Scholar

  • [23]

    L. Grassi, G. Maisetta, S. Esin, G. Batoni. Front. Microbiol. 8, 2409 (2017).CrossrefGoogle Scholar

  • [24]

    A. Reinhardt, I. Neundorf. Int. J. Mol. Sci. 17, 701 (2016).CrossrefGoogle Scholar

  • [25]

    J. O’Neill. Rev. Antimicrob. Resist. 20, 1 (2014).Google Scholar

  • [26]

    Antibiotic Resistance Threats in the United States, U.S.D.H.H.S, Centers for Disease Control and Prevention (2013).Google Scholar

  • [27]

    Global Priority List of Antibiotic-Resistant Bacteria to Guide Research, Discovery, and Development of New Antibiotics, World Health Organization (WHO), Geneva, Switzerland (2017).Google Scholar

  • [28]

    L. Peterson. Clin. Infect. Dis. 49, 992 (2009).CrossrefGoogle Scholar

  • [29]

    K. Kaye, J. Pogue. Pharmacotheraphy 35, 949 (2015).CrossrefGoogle Scholar

  • [30]

    S. Lam, N. O’Brien Simpson, N. Pantarat, A. Sulistio, E. H. H. Wong, Y.-Y. Chen, J. C. Lenzo, J. A. Holden, A. Blencowe, E. C. Reynolds, G. G. Qiao. Nat. Microbiol. 1, 16162 (2016).CrossrefGoogle Scholar

  • [31]

    J. Sun, Z. Deng, A. Yan. Biochem. Biophys. Res. Commun. 453, 254 (2014).CrossrefGoogle Scholar

  • [32]

    D. P. O’Connell. Trends Microbiol. (Regular ed.) 9, 410 (2001).Google Scholar

  • [33]

    J. Munita, C. Arias. Microbiology Spectr. 4, (2016).Google Scholar

  • [34]

    K. Long, B. Vester. Antimicrob. Agents Chemother. 56, 603 (2012).CrossrefGoogle Scholar

  • [35]

    P. A. Lambert. Adv. Drug Del. Rev. 57, 1471 (2005).CrossrefGoogle Scholar

  • [36]

    G. Wright. BMC Biol. 8, 123 (2010).CrossrefGoogle Scholar

  • [37]

    L. Zaffiri, J. Gardner, L. H. Toledo-Pereyra. J. Invest. Surg. 25, 67 (2012).CrossrefGoogle Scholar

  • [38]

    P. Neushul. J. Hist. Med. Allied Sci. 48, (1993).Google Scholar

  • [39]

    Maker of the Miracle Mould. http://www.abc.net.au/science/slab/florey/story.htm (accessed Jul 5 2018).

  • [40]

    75 Years of Penicillin in People, University of Oxford. http://www.ox.ac.uk/news/science-blog/75-years-penicillin-people (accessed Jul 5 2018).

  • [41]

    D. Flaherty. Immunology for Pharmacy, Elsevier Health Sciences (2014).Google Scholar

  • [42]

    L. Shargel, A. H. Mutnick. Comprehensive Pharmacy Review, Lippincott Williams & Wilkins (2007).Google Scholar

  • [43]

    S. Rossi. Australian Medicines Handbook, AMH Pty Ltd (2004).Google Scholar

  • [44]

    R. C. Owens. Critical Care 12, S3 (2008).Google Scholar

  • [45]

    A. Dalhoff, N. Janjic, R. Echols. Biochem. Pharmacol. 71, 1085 (2006).CrossrefGoogle Scholar

  • [46]

    C. Walsh, G. Wright. Chem. Rev. 105, 391 (2005).CrossrefGoogle Scholar

  • [47]

    C. Thornsberry. Amer. J. Med. 79, 14 (1985).Google Scholar

  • [48]

    M. Tulkens. Antimicrob. Agents Chemother. 43, 727 (1999).CrossrefGoogle Scholar

  • [49]

    P. E. Reynolds. Eur. J. Clin. Microbiol. Infect. Dis. 8, 943 (1989).CrossrefGoogle Scholar

  • [50]

    M. Fines, R. Leclercq. J. Antimicrob. Chemother. 45, 797 (2000).CrossrefGoogle Scholar

  • [51]

    S. C. Piscitelli, L. H. Danziger, K. A. Rodvold. Clin. Pharm. 11, 137 (1992).Google Scholar

  • [52]

    R. L. Momparler, M. Karon, S. E. Siegel, F. Avila. Cancer Res. 36, 2891 (1976).Google Scholar

  • [53]

    E. P. Quinlivan, J. McPartlin, D. G. Weir, J. Scott. FASEB J. 14, 2519 (2000).CrossrefGoogle Scholar

  • [54]

    A. Bayer, T. Schneider, H.-G. Sahl. Ann. N.Y. Acad. Sci. 1277, 139 (2013).CrossrefGoogle Scholar

  • [55]

    H. Marston, D. Dixon, J. Knisely, T. N. Palmore, A. S. Fauci. J. Am. Med. Assoc. 316, 1193 (2016).CrossrefGoogle Scholar

  • [56]

    J. Ruiz. J. Antimicrob. Chemother. 51, 1109 (2003).CrossrefGoogle Scholar

  • [57]

    M. Fernández, S. Conde, J. de la Torre, C. Molina-Santiago, J. L. Ramos, E. Duque. Antimicrob. Agents Chemother. 56, 1001 (2012).CrossrefGoogle Scholar

  • [58]

    L. G. Suhrland, A. S. Weisberger. Arch. Internal Med. 112, 747 (1963).CrossrefGoogle Scholar

  • [59]

    K. K. Kumarasamy, M. A. Toleman, T. R. Walsh, J. Bagaria, F. Butt, R. Balakrishnan, U. Chaudhary, M. Doumith, C. G. Giske, S. Irfan, P. Krishnan, A. V. Kumar, S. Maharjan, S. Mushtaq, T. Noorie, D. L. Paterson, A. Pearson, C. Perry, R. Pike, B. Rao, U. Ray, J. B. Sarma, M. Sharma, E. Sheridan, M. A. Thirunarayan, J. Turton, S. Upadhyay, M. Warner, W. Welfare, D. M. Livermore, N. Woodford. Lancet Infect. Dis. 10, 597 (2010).CrossrefGoogle Scholar

  • [60]

    Y. -Y. Liu, Y. Wang, T. R. Walsh, L. X. Yi, R. Zhang, J. Spencer, Y. Doi, G. Tian, B. Dong, X. Huang, L. F. Yu, D. Gu, H. Ren, X. Chen, L. Lv, D. He, H. Zhou, Z. Liang, J. H. Liu, J. Shen. Lancet Infect. Dis. 16, 161 (2016).CrossrefGoogle Scholar

  • [61]

    B. Müller, S. Borrell, G. Rose, S. Gagneux. Trends Genetics (Regular ed.) 29, 160 (2013).Google Scholar

  • [62]

    R. E. W. Hancock, G. Diamond. Trends Microbiol. (Regular ed.) 8, 402 (2000).Google Scholar

  • [63]

    J. Nissen Meyer, I. Nes. Arch. Microbiol. 167, 67 (1997).CrossrefGoogle Scholar

  • [64]

    A. Ruzin, G. Singh, A. Severin, Y. Yang, R. G. Dushin, A. G. Sutherland, A. Minnick, M. Greenstein, M. K. May, D. M. Shlaes, P. A. Bradford. Antimicrob. Agents Chemother. 48, 728 (2004).CrossrefGoogle Scholar

  • [65]

    J. R. Knox, R. F. Pratt. Antimicrob. Agents Chemother. 34, 1342 (1990).CrossrefGoogle Scholar

  • [66]

    A. Giuliani, G. Pirri, A. Bozzi, A. Di Giulio, M. Aschi, A. C. Rinaldi. Cell. Mol. Life Sci. 65, 2450 (2008).CrossrefGoogle Scholar

  • [67]

    R. E. Hancock, D. S. Chapple. Antimicrob. Agents Chemother. 43, 1317 (1999).CrossrefGoogle Scholar

  • [68]

    N. Papo, Y. Shai. Peptides (New York, NY: 1980) 24, 1693 (2003).Google Scholar

  • [69]

    L. Zhang, A. Rozek, R. E. Hancock. J. Biol. Chem. 276, 35714 (2001).CrossrefGoogle Scholar

  • [70]

    Y. Shai. Biochim. Biophys. Acta Biomembranes 1462, 55 (1999).CrossrefGoogle Scholar

  • [71]

    Y. Shai. Biopolymers 66, 236 (2002).CrossrefGoogle Scholar

  • [72]

    S. J. Ludtke, K. He, W. T. Heller, T. A. Harroun, L. Yang, H. W. Huang. Biochemistry 35, 13723 (1996).CrossrefGoogle Scholar

  • [73]

    K. Brogden. Nat. Rev. Microbiol. 3, 238 (2005).CrossrefGoogle Scholar

  • [74]

    L. K. Tamm. Protein-Lipid Interactions: From Membrane Domains to Cellular Networks. Wiley (2006).Google Scholar

  • [75]

    A. Ramamoorthy, D.-K. Lee, T. Narasimhaswamy, R. P. R. Nanga. Biochim. Biophys. Acta Biomembranes 1798, 223 (2010).CrossrefGoogle Scholar

  • [76]

    D. Sengupta, H. Leontiadou, A. Mark, S.-J. Marrink. Biochim. Biophys. Acta Biomembranes 1778, 2308 (2008).CrossrefGoogle Scholar

  • [77]

    W. C. Wimley. ACS Chem. Biol. 5, 905 (2010).CrossrefGoogle Scholar

  • [78]

    L. Yang, T. A. Harroun, T. M. Weiss, L. Ding, H. W. Huang. Biophys. J. 81, 1475 (2001).CrossrefGoogle Scholar

  • [79]

    W. Li, N. M. O’Brien-Simpson, J. Tailhades, N. Pantarat, R. M. Dawson, L. Otvos Jr., E. C. Reynolds, F. Separovic, M. A. Hossain, J. D. Wade. Chem. Biol. 22, 1250 (2015).CrossrefGoogle Scholar

  • [80]

    T. J. Falla, D. N. Karunaratne, R. E. Hancock. J. Biol. Chem. 271, 19298 (1996).CrossrefGoogle Scholar

  • [81]

    C. P. J. M. Brouwer, S. J. P. Bogaards, M. Wulferink, M. P. Velders, M. M. Welling. Peptides (New York, NY: 1980) 27, 2585 (2006).Google Scholar

  • [82]

    H. Chen, C. Liu, D. Chen, K. Madrid, S. Peng, X. Dong, M. Zhang, Y. Gu. Mol. Pharm. 12, 2505 (2015).CrossrefGoogle Scholar

  • [83]

    S. Nuding, T. Frasch, M. Schaller, E. F. Stange, L. T. Zabe. Antimicrob. Agents Chemother. 58, 5719 (2014).CrossrefGoogle Scholar

  • [84]

    S. Deshayes, W. Xian, N. W. Schmidt, S. Kordbacheh, J. Lieng, J. Wang, S. Zarmer, S. St. Germain, L. Voyen, J. Thulin, G. C. L. Wong, A. M. Kasko. Bioconjugate Chem. 28, 793 (2017).CrossrefGoogle Scholar

  • [85]

    G. E. Magoulas, O. N. Kostopoulou, T. Garnelis, C. M. Athanassopoulos, G. G. Kournoutou, M. Leotsinidis, G. P. Dinos, D. Papaioannou, D. L. Kalpaxis. Biorg. Med. Chem. 23, 3163 (2015).CrossrefGoogle Scholar

  • [86]

    J. A. Chmielewski. Dual-Action, Unnatural Proline-Rich Peptides as Antibiotic Agents and Methods Thereof. US Patent 9,533,975 (2017).Google Scholar

  • [87]

    S. S. Lateef, S. Gupta, L. P. Jayathilaka, S. Krishnanchettiar, J.-S. Huang, B.-S. Lee. J. Biomol. Techniques 18, 173 (2007).Google Scholar

  • [88]

    M. Zorko, U. Langel. Adv. Drug Del. Rev. 57, 529 (2005).CrossrefGoogle Scholar

  • [89]

    W. Li, N. M. O’Brien Simpson, J. A. Holden, L. Otvos, E. C. Reynolds, F. Separovic, M. Akhter Hossain, J. D. Wade. Peptide Science 110, e24059 (2018).CrossrefGoogle Scholar

  • [90]

    K. A. Ghaffar, W. M. Hussein, Z. G. Khalil, R. J. Capon, M. Skwarczynski, I. Toth. Curr. Drug Del. 12, 108 (2015).CrossrefGoogle Scholar

  • [91]

    A. Brezden, M. F. Mohamed, M. Nepal, J. S. Harwood, J. Kuriakose, M. N. Seleem, J. Chmielewski. J. Am. Chem. Soc. 138, 10945 (2016).CrossrefGoogle Scholar

  • [92]

    C. J. Arnusch, R. J. Pieters, E. Breukink. PLoS One 7, e39768 (2012).CrossrefGoogle Scholar

  • [93]

    G. Yu, D. Baeder, R. Regoes, J. Rolff. Antimicrob. Agents Chemother. 60, 1717 (2016).CrossrefGoogle Scholar

  • [94]

    S. Li, R. Roberts. Chem. Biol. 10, 233 (2003).CrossrefGoogle Scholar

  • [95]

    C. Riber, A. A. A. Smith, A. Zelikin. Adv. Healthc. Mater. 4, 1887 (2015).CrossrefGoogle Scholar

  • [96]

    M. Kohanski, D. Dwyer, J. Collins. Nat. Rev. Microbiol. 8, 423 (2010).CrossrefGoogle Scholar

  • [97]

    T. Bollenbach. Curr. Opin. Microbiol. 27, 1 (2015).CrossrefGoogle Scholar

  • [98]

    R. Worthington, C. Melander. Trends Biotechnol. (Regular ed.) 31, 177 (2013).Google Scholar

  • [99]

    V. W. L. Ng, X. Ke, A. L. Z. Lee, J. L. Hedrick, Y. Y. Yang. Adv. Mater. 25, 6730 (2013).CrossrefGoogle Scholar

  • [100]

    G. Wright. Trends Microbiol, (Regular ed.) 24, 862 (2016).Google Scholar

  • [101]

    R. E. W. Hancock, H.-G. Sahl. Nat. Biotechnol. 24, 1551 (2006).CrossrefGoogle Scholar

  • [102]

    E. Gill, O. Franco, R. E. W. Hancock. Chem. Biol. Drug Des. 85, 56 (2015).CrossrefGoogle Scholar

  • [103]

    S. Lam, N. M. O’Brien Simpson, N. Pantarat, A. Sulistio, E. H. Wong, Y. Y. Chen, J. C. Lenzo, J. A. Holden, A. Blencowe, E. C. Reynolds, G. G. Qiao. Nat. Microbiol. 1, 16162 (2016).CrossrefGoogle Scholar

  • [104]

    A. F. Chu Kung, R. Nguyen, K. N. Bozzelli, M. Tirrell. J. Colloid Interface Sci. 345, 160 (2010).CrossrefGoogle Scholar

  • [105]

    T. Dai, Y.-Y. Huang, M. Hamblin. Photodiagnosis Photodyn. Ther. 6, 170 (2009).CrossrefGoogle Scholar

  • [106]

    J. Bandow, N. Metzler Nolte. ChemBioChem 10, 2847 (2009).CrossrefGoogle Scholar

  • [107]

    N. M. O’Brien-Simpson, R. Hoffmann, C. S. B. Chia, J. D. Wade. Front. Chem. 6, 13 (2018).CrossrefGoogle Scholar

About the article

Published Online: 2019-01-29

Published in Print: 2019-02-25

Funding Source: National Health and Medical Research Council

Award identifier / Grant number: APP1117483

Award identifier / Grant number: APP1142472

National Health and Medical Research Council, Funder Id: 10.13039/501100000925, Grant Number: APP1117483, National Health and Medical Research Council, Funder Id: 10.13039/501100000925, Grant Number: APP1142472.

Citation Information: Pure and Applied Chemistry, Volume 91, Issue 2, Pages 199–209, ISSN (Online) 1365-3075, ISSN (Print) 0033-4545, DOI: https://doi.org/10.1515/pac-2018-0707.

Export Citation

©2019 IUPAC & De Gruyter. This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. For more information, please visit: http://creativecommons.org/licenses/by-nc-nd/4.0/.Get Permission

Comments (0)

Please log in or register to comment.
Log in