The Role of Counter-Anions on Cationic Antimicrobial Agents

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Cheol Min Lee Hyun Jun Kim Shreya Timilsina Ronny Priefer


Even though a myriad of antimicrobial agents have been developed over the decades, resistant mechanisms continually break through, ultimately increasing our mortality and fears. Significant efforts have been made to evade these pathogenic resistances by developing novel antimicrobial agents which work on different targets. One possible, simple solution that has also been investigated has been to modify the counter-anion of cationic-based drugs. Although a multitude of studies have evaluated the efficacy of the active cationic agent, some have also explored the often-neglected influence of the counter-anion. Understanding the role of the counter-anions may provide new antimicrobial agents and an alternative approach to quell antimicrobial resistance. This review focuses on the various studies that have either directly or in-directly evaluated the role of the counter-anion on antimicrobial activities. Indeed, certain cationic-based agents display significant alternation in their activity when paired with the correct anion.

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LEE, Cheol Min et al. The Role of Counter-Anions on Cationic Antimicrobial Agents. Medical Research Archives, [S.l.], v. 10, n. 3, mar. 2022. ISSN 2375-1924. Available at: <>. Date accessed: 28 nov. 2022. doi:
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1. World Health Organization (WHO) Top 10 causes of death. WHO; 9 December 2020., [accessed 3 August 2021].
2. Gould IM. A review of the role of antibiotic policies in the control of antibiotic resistance. J Antimicrob Chemother. 1999;43:459-65. doi:10.1093/jac/43.4.459.
3. Hawkey PM. The origins and molecular basis of antibiotic resistance. BMJ. 1998;317(7159):657-660. doi:10.1136/bmj.317.7159.657.
4. Cantón R, Morosini MI. Emergence and spread of antibiotic resistance following exposure to antibiotics. FEMS Microbiol Rev. 2011;35(5):977-991. doi:10.15620/cdc:82532.
5. CDC. Antibiotic Resistance Threats in the United States, 2019. Atlanta, GA: U.S. Department of Health and Human Services, CDC; 2019. doi:10.15620/cdc:82532.
6. WHO Antibiotic Resistance. WHO; 31 July 2020., [accessed 13 July 2021].
7. AMR Review Background; [accessed July 17, 2021].
8. Mendelson M, Matsoso MP. The World Health Organization Global Action Plan for antimicrobial resistance. S Afr Med J. 2015;105(5):325. Published 2015 Apr 6. doi:10.7196/samj.9644.
9. WHO Global Antimicrobial Resistance and Use Surveillance System (GLASS) Report: Early implementation 2020. WHO; 2020., [accessed 15 July 2021].
10. AMR Action Fund About us; April 30, 2021., [accessed July 17, 2021].
11. Munita JM, Arias CA. Mechanisms of Antibiotic Resistance. Microbiol Spectr 2016;4(2):1-24. doi:10.1128/microbiolspec.VMBF-0016-2015.
12. Lister PD. Beta-lactamase inhibitor combinations with extended-spectrum penicillins: factors influencing antibacterial activity against Enterobacteriaceae and Pseudomonas aeruginosa. Pharmacotherapy 2000;20(9 Pt 2):213S-228S. doi: 10.1592/phco.20.14.213S.35045.
13. Drawz SM, Bonomo RA. Three decades of beta-lactamase inhibitors. Clin Microbiol Rev. 2010;23(1):160-201. doi:10.1128/CMR.00037-09.
14. Isik M, Tan JP, Ono RJ, et al. Tuning the Selectivity of Biodegradable Antimicrobial Cationic Polycarbonates by Exchanging the Counter-Anion. Macromol Biosci. 2016;16(9):1360-1367. doi:10.1002/mabi.201600090.
15. Ingalsbe ML, Denis JD, McGahan ME, et al. Development of a novel expression, ZI MAX/K ZI, for determination of the counter-anion effect on the antimicrobial activity of tetrabutylammonium salts. Bioorg Med Chem Lett. 2009;19(17):4984-4987. doi: 10.1016/j.bmcl.2009.07.066.
16. Kanazawa A, Ikeda T, Endo T. Polymeric phosphonium salts as a novel class of cationic biocides. VII. Synthesis and antibacterial activity of polymeric phosphonium salts and their model compounds containing long alkyl chains. J Appl Polym Sci 1994;53:1237-44 doi.10.1002/app.1994.070530910.
17. Collins KD. Charge density-dependent strength of hydration and biological structure. Biophys J. 1997;72(1):65-76. doi:10.1016/S0006-3495(97)78647-8.
18. Yoshino N, Sugaya S, Nakamura T, et al. Synthesis and antimicrobial activity of quaternary ammonium silane coupling agents. J Oleo Sci. 2011;60(8):429-438. doi:10.5650/jos.60.429.
19. Brunel F, Lautard C, di Giorgio C, et al. Antibacterial activities of mono-, di- and tri-substituted triphenylamine-based phosphonium ionic liquids. Bioorg Med Chem Lett. 2018;28(5):926-929. doi:10.1016/j.bmcl.2018.01.057.
20. Chen CZ, Beck-Tan NC, Dhurjati P, et al. Quaternary ammonium functionalized poly(propylene imine) dendrimers as effective antimicrobials: structure-activity studies. Biomacromolecules. 2000;1(3):473-480. doi:10.1021/bm0055495.
21. Walker AJ, Jassim SA, Holah JT, et al. Bioluminescent Listeria monocytogenes provide a rapid assay for measuring biocide efficacy. FEMS Microbiol Lett. 1992;70(3):251-255. doi:10.1016/0378-1097(92)90706-t.
22. Rayner-Canham G, Overton T. Descriptive Inorganic Chemistry. 5th ed. New York, NY: Freeman; 2010.
23. Zhou X, Hu S, Wang Y, et al. The surface adsorption, aggregate structure and antibacterial activity of Gemini quaternary ammonium surfactants with carboxylic counterions. Royal Society Open Science. 2019;6(8). doi:10.1098/rsos.190378.
24. Savić ND, Petković BB, Vojnovic S, et al. Dinuclear silver(i) complexes with a pyridine-based macrocyclic type of ligand as antimicrobial agents against clinically relevant species: the influence of the counteranion on the structure diversification of the complexes. Dalton Trans. 2020;49(31):10880-10894. doi:10.1039/d0dt01272f.
25. Kalinowska-Lis U, Felczak A, Checinska L, et al. Influence of selected inorganic counter-ions on the structure and antimicrobial properties of silver(I) complexes with imidazole-containing ligands. New Journal of Chemistry. 2016;40:694-794. doi:10.1039/C5NJ02514A.
26. Castiglia F, Zevolini F, Riolo G, et al. NMR Study of the Secondary Structure and Biopharmaceutical Formulation of an Active Branched Antimicrobial Peptide. Molecules. 2019;24(23):4290. doi:10.3390/molecules24234290.
27. Gaussier H, Morency H, Lavoie MC, et al. Replacement of trifluoroacetic acid with HCl in the hydrophobic purification steps of pediocin PA-1: a structural effect. Appl Environ Microbiol. 2002;68(10):4803-4808. doi:10.1128/AEM.68.10.4803-4808.2002.
28. Blondelle SE, Ostresh JM, Houghten RA, et al. Induced conformational states of amphipathic peptides in aqueous/lipid environments. Biophys J. 1995;68(1):351-359. doi:10.1016/S0006-3495(95)80194-3.
29. Cinelli S, Spinozzi F, Itri R, et al. Structural characterization of the pH-denatured states of ferricytochrome-c by synchrotron small angle X-ray scattering. Biophys J. 2001;81(6):3522-3533. doi:10.1016/S0006-3495(01)75983-8.
30. Sikora K, Jaśkiewicz M, Neubauer D, et al. Counter-ion effect on antistaphylococcal activity and cytotoxicity of selected antimicrobial peptides. Amino Acids. 2018;50(5):609-619. doi:10.1007/s00726-017-2536-9.
31. Salama A, Hasanin M, Hesemann P. Synthesis and antimicrobial properties of new chitosan derivatives containing guanidinium groups. Carbohydr Polym. 2020;241:116363. doi:10.1016/j.carbpol.2020.116363.
32. Monier M, Abdel-Latif DA, Youssef I. Preparation of ruthenium (III) ion-imprinted beads based on 2-pyridylthiourea modified chitosan. J Colloid Interface Sci. 2018;513:266-278. doi:10.1016/j.jcis.2017.11.004.
33. Salama A. Chitosan based hydrogel assisted spongelike calcium phosphate mineralization for in-vitro BSA release. Int J Biol Macromol. 2018;108:471-476. doi:10.1016/j.ijbiomac.2017.12.035.
34. Salama A, El-Sakhawy M. Preparation of polyelectrolyte/calcium phosphate hybrids for drug delivery application. Carbohydrate Polymer. 2014;113:500-506. doi:10.1016/j.carbpol.2014.07.022.
35. Cacic M, Trkovnik M, Cacic F, et al. Synthesis and antimicrobial activity of some derivatives of (7-hydroxy-2-oxo-2H-chromen-4-yl)-acetic acid hydrazide. Molecules. 2006;11(2):134-147. doi:10.3390/11010134.
36. Chung Y-S, Lee K-K, Kim J-W. Durable Press and Antimicrobial Finishing of Cotton Fabrics with a Citric Acid and Chitosan Treatment. Textile Research Journal. 1998;68(10):772-775. doi:10.1177/004051759806801011.
37. Kim E, Lee SH, Lee SJ, et al. New antibacterial-core structures based on styryl quinolinium. Food Sci Biotechnol. 2017;26(2):521-529. doi:10.1007/s10068-017-0072-8.
38. Gilbert P, Moore LE. Cationic antiseptics: diversity of action under a common epithet. J Appl Microbiol. 2005;99(4):703-715. doi:10.1111/j.1365-2672.2005.02664.x.
39. Houtsma PC, Kusters BJ, de Wit JC, et al. Modelling growth rates of Listeria innocua as a function of lactate concentration. Int J Food Microbiol. 1994;24(1-2):113-123. doi:10.1016/0168-1605(94)90111-2.
40. Sharma SK, Chauhan GS, Gupta R, et al. Tuning anti-microbial activity of poly(4-vinyl 2-hydroxyethyl pyridinium) chloride by anion exchange reactions. J Mater Sci Mater Med. 2010;21(2):717-724. doi:10.1007/s10856-009-3932-9.
41. Garg G, Chauhan GS, Gupta R, et al. Anion effects on anti-microbial activity of poly[1-vinyl-3-(2-sulfoethyl imidazolium betaine)]. J Colloid Interface Sci. 2010;344(1):90-96. doi:10.1016/j.jcis.2009.12.016.
42. Paslay LC, Abel BA, Brown TD, et al. Antimicrobial poly(methacrylamide) derivatives prepared via aqueous RAFT polymerization exhibit biocidal efficiency dependent upon cation structure. Biomacromolecules. 2012;13(8):2472-2482. doi:10.1021/bm3007083.

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