Antibacterial low molecular weight cationic polymers: Dissecting the contribution of hydrophobicity, chain length and charge to activity

James Lynden Grace, Johnny X Huang, S.-E. Cheah, Nghia Truong Phuoc, Matthew A Cooper, Jian Li, T.P. Davis, J.F. Quinn, T. Velkov, M.R. Whittaker

Research output: Contribution to journalArticleResearchpeer-review

Abstract

The balance of cationicity and hydrophobicity can profoundly affect the performance of antimicrobial polymers. To this end a library of 24 cationic polymers with uniquely low degrees of polymerization was synthesized via Cu(0)-mediated polymerization, using three different cationic monomers and two initiators: providing two different hydrocarbon chain tail lengths (C2 and C12). The polymers exhibited structure-dependent antibacterial activity when tested against a selection of bacteria, viz., Staphylococcus aureus ATCC 29213, Klebsiella pneumoniae ATCC 13883, Acinetobacter baumannii ATCC 19606, and Pseudomonas aeruginosa ATCC 27853 as a representative palette of Gram-positive and Gram-negative ESKAPE pathogens. The five best-performing polymers were identified for additional testing against the polymyxin-resistant A. baumannii ATCC 19606R strain. Polymers having the lowest DP and a C12 hydrophobic tail were shown to provide the broadest antimicrobial activity against the bacteria panel studied as evidenced by lower minimum inhibitory concentrations (MICs). An optimal polymer composition was identified, and its mechanism of action investigated via membrane permeability testing against Escherichia coli. Membrane disruption was identified as the most probable mechanism for bacteria cell killing.

Original languageEnglish
Pages (from-to)15469-15477
Number of pages9
JournalRSC Advances
Volume6
Issue number19
DOIs
Publication statusPublished - 2016

Cite this

@article{f9fd71700c2d4e1c8ab5b0b3e3afe3ba,
title = "Antibacterial low molecular weight cationic polymers: Dissecting the contribution of hydrophobicity, chain length and charge to activity",
abstract = "The balance of cationicity and hydrophobicity can profoundly affect the performance of antimicrobial polymers. To this end a library of 24 cationic polymers with uniquely low degrees of polymerization was synthesized via Cu(0)-mediated polymerization, using three different cationic monomers and two initiators: providing two different hydrocarbon chain tail lengths (C2 and C12). The polymers exhibited structure-dependent antibacterial activity when tested against a selection of bacteria, viz., Staphylococcus aureus ATCC 29213, Klebsiella pneumoniae ATCC 13883, Acinetobacter baumannii ATCC 19606, and Pseudomonas aeruginosa ATCC 27853 as a representative palette of Gram-positive and Gram-negative ESKAPE pathogens. The five best-performing polymers were identified for additional testing against the polymyxin-resistant A. baumannii ATCC 19606R strain. Polymers having the lowest DP and a C12 hydrophobic tail were shown to provide the broadest antimicrobial activity against the bacteria panel studied as evidenced by lower minimum inhibitory concentrations (MICs). An optimal polymer composition was identified, and its mechanism of action investigated via membrane permeability testing against Escherichia coli. Membrane disruption was identified as the most probable mechanism for bacteria cell killing.",
author = "Grace, {James Lynden} and Huang, {Johnny X} and S.-E. Cheah and {Truong Phuoc}, Nghia and Cooper, {Matthew A} and Jian Li and T.P. Davis and J.F. Quinn and T. Velkov and M.R. Whittaker",
note = "Export Date: 25 July 2016 CODEN: RSCAC Correspondence Address: Whittaker, M.R.; Australian Research Council, Centre of Excellence in Convergent Bio-Nano Science and Technology, 381 Royal Pde, Australia; email: michael.whittaker@monash.edu References: (2014) CDC-Get Smart: Know When Antibiotics Work 2013, , http://www.cdc.gov/getsmart/antibiotic-use/antibiotic-resistance-faqs.html#how-bacteria-resist, 17 April; Nolte, O., (2014) Protein Pept. Lett., 21, pp. 330-335; Rice, L.B., Challenges in identifying new antimicrobial agents effective for treating infections with Acinetobacter baumannii and Pseudomonas aeruginosa (2006) Clin. Infect. Dis., 43, pp. S100-S105; Chambers, H.F., (2001) Postgrad. Med., 109, pp. 43-50; Who, (2014) ANTIMICROBIAL RESISTANCE Global Report on Surveillance, , WHO Library; Ling, L.L., Schneider, T., Peoples, A.J., Spoering, A.L., Engels, I., Conlon, B.P., (2015) Nature, 517, pp. 455-459; Yeung, A.T.Y., Gellatly, S.L., Hancock, R.E.W., (2011) Cell. Mol. Life Sci., 68, pp. 2161-2176; Nederberg, F., Zhang, Y., Tan, J.P., Xu, K., Wang, H., Yang, C., (2011) Nat. Chem., 3, pp. 409-414; Locock, K.E.S., Michl, T.D., Valentin, J.D.P., Vasilev, K., Hayball, J.D., Qu, Y., (2013) Biomacromolecules, 14, pp. 4021-4031; Giuliani, A., Pirri, G., Nicoletto, S.F., (2007) Cent. Eur. J. Biol., 2, pp. 1-33; Kuroda, K., Caputo, G.A., (2013) Wiley Interdiscip. Rev.: Nanomed. Nanobiotechnol., 5, pp. 49-66; Kenawy, E.R., Worley, S.D., Broughton, R., (2007) Biomacromolecules, 8, pp. 1359-1384; Timofeeva, L., Kleshcheva, N., (2011) Appl. Microbiol. Biotechnol., 89, pp. 475-492; Mowery, B.P., Lindner, A.H., Weisblum, B., Stahl, S.S., Gellman, S.H., (2009) J. Am. Chem. Soc., 131, pp. 9735-9745; Michl, T.D., Locock, K.E.S., Stevens, N.E., Hayball, J.D., Vasilev, K., Postma, A., (2014) Polym. Chem., 5, pp. 5813-5822; Gody, G., Maschmeyer, T., Zetterlund, P.B., Perrier, S., (2013) Nat. Commun., 4, pp. 1-9; Anastasaki, A., Nikolaou, V., Nurumbetov, G., Wilson, P., Kempe, K., Quinn, J.F., Davis, T.P., Haddleton, D.M., (2015) Chem. Rev.; Boyer, C., Zetterlund, P.B., Whittaker, M.R., (2014) J. Polym. Sci., Part A: Polym. Chem., 52, pp. 2083-2098; Boyer, C., Soeriyadi, A.H., Zetterlund, P.B., Whittaker, M.R., (2011) Macromolecules, 44, pp. 8028-8033; Soeriyadi, A.H., Boyer, C., Nystr{\"o}m, F., Zetterlund, P.B., Whittaker, M.R., (2011) J. Am. Chem. Soc., 133, pp. 11128-11131; Lee, J., (2007), PhD thesis, University of North CarolinaMartin, T.P., (2007), PhD thesis, Massachusetts Institute of TechnologyRawlinson, L.A.B., Ryan, S.M., Mantovani, G., Syrett, J.A., Haddleton, D.M., Brayden, D.J., (2010) Biomacromolecules, 11, pp. 443-453; Zuo, H.J., Wu, D.C., Fu, R.W., (2010) Polym. J., 42, pp. 766-771; Lin, S., Wu, J.H., Jia, H.Q., Hao, L.M., Wang, R.Z., Qi, J.C., (2013) RSC Adv., 3, pp. 20758-20764; Dutta, P., Dey, J., Shome, A., Das, P.K., (2011) Int. J. Pharm., 414, pp. 298-311; Talbot, G.H., Bradley, J., Edwards, J.E., Gilbert, D., Scheld, M., Bartlett, J.G., (2006) Clin. Infect. Dis., 42, pp. 657-668; Boucher, H.W., Talbot, G.H., Bradley, J.S., Edwards, J.E., Gilbert, D., Rice, L.B., (2009) Clin. Infect. Dis., 48, pp. 1-12; Ciampolini, M., Nardi, N., (1966) Inorg. Chem., 5, pp. 41-44; Anderson, R.C., Hancock, R.E.W., Yu, P.L., (2004) Antimicrob. Agents Chemother., 48, pp. 673-676; Helander, I.M., Mattila-Sandholm, T., (2000) J. Appl. Microbiol., 88, pp. 213-219; Dathe, M., Wieprecht, T., (1999) Biochim. Biophys. Acta, Biomembr., 1462, pp. 71-87; B{\"u}t{\"u}n, V., Armes, S.P., Billingham, N.C., (2001) Macromolecules, 34, pp. 1148-1159; Lu, G., Wu, D., Fu, R., (2007) React. Funct. Polym., 67, pp. 355-366; Tashiro, T., (2001) Macromol. Mater. Eng., 286, pp. 63-87; Li, J., Nation, R.L., Owen, R.J., Wong, S., Spelman, D., Franklin, C., (2007) Clin. Infect. Dis., 45, pp. 594-598; Nikaido, H., (2003) Microbiol. Mol. Biol. Rev., 67, pp. 593-656; Moffatt, J.H., Harper, M., Harrison, P., Hale, J.D.F., Vinogradov, E., Seemann, T., (2010) Antimicrob. Agents Chemother., 54, pp. 4971-4977; Zhang, L.J., Dhillon, P., Yan, H., Farmer, S., Hancock, R.E.W., (2000) Antimicrob. Agents Chemother., 44, pp. 3317-3321; Wang, Y., Zhou, Z., Zhu, J., Tang, Y., Canady, T.D., Chi, E.Y., (2011) Polymers, 3, pp. 1199-1214; Helander, I.M., Nurmiaho-Lassila, E.L., Ahvenainen, R., Rhoades, J., Roller, S., (2001) Int. J. Food Microbiol., 71, pp. 235-244; Johnson, L., Mulcahy, H., Kanevets, U., Shi, Y., Lewenza, S., (2012) J. Bacteriol., 194, pp. 813-826; Rub{\'e}n, D.L., Tejero, D.L., L{\'o}pez-Fabal, F., G{\'o}mez-Garc{\'e}s, J.L., Fern{\'a}ndez-Garc{\'i}a, M., (2015) Polym. Chem., 6, pp. 3449-3459; Punia, A., Mancuso, A., Banerjee, P., Yang, N.-L., (2015) ACS Macro Lett., 4, pp. 426-430; Palermo, E.F., Kuroda, K., (2010) Appl. Microbiol. Biotechnol., 87, pp. 1605-1615; Hwang, T.L., Aljuffali, I.A., Lin, C.F., Chang, Y.T., Fang, J.Y., (2015) Int. J. Nanomed., 10, pp. 371-385; Fischer, D., Li, Y.X., Ahlemeyer, B., Krieglstein, J., Kissel, T., (2003) Biomaterials, 24, pp. 1121-1131; Truong, N.P., Jia, Z.F., Burges, M., McMillan, N.A.J., Monteiro, M.J., (2011) Biomacromolecules, 12, pp. 1876-1882; Lv, H.T., Zhang, S.B., Wang, B., Cui, S.H., Yan, J., (2006) J. Controlled Release, 114, pp. 100-109; Shannahan, J.H., Lai, X.Y., Ke, P.C., Podila, R., Brown, J.M., Witzmann, F.A., (2013) PLoS One, 8, p. 10; Wang, F.J., Yu, L., Monopoli, M.P., Sandin, P., Mahon, E., Salvati, A., (2013) Nanomedicine, 9, pp. 1159-1168; Ilic, N., Novkovic, M., Guida, F., Xhindoli, D., Benincasa, M., Tossi, A., (2013) Biochim. Biophys. Acta, Biomembr., 1828, pp. 1004-1012; Li, Y.M., Bionda, N., Yongye, A., Geer, P., Stawikowski, M., Cudic, P., (2013) ChemMedChem, 8, pp. 1865-1872",
year = "2016",
doi = "10.1039/c5ra24361k",
language = "English",
volume = "6",
pages = "15469--15477",
journal = "RSC Advances",
issn = "2046-2069",
publisher = "The Royal Society of Chemistry",
number = "19",

}

Antibacterial low molecular weight cationic polymers : Dissecting the contribution of hydrophobicity, chain length and charge to activity. / Grace, James Lynden; Huang, Johnny X; Cheah, S.-E.; Truong Phuoc, Nghia; Cooper, Matthew A; Li, Jian; Davis, T.P.; Quinn, J.F.; Velkov, T.; Whittaker, M.R.

In: RSC Advances, Vol. 6, No. 19, 2016, p. 15469-15477.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Antibacterial low molecular weight cationic polymers

T2 - Dissecting the contribution of hydrophobicity, chain length and charge to activity

AU - Grace, James Lynden

AU - Huang, Johnny X

AU - Cheah, S.-E.

AU - Truong Phuoc, Nghia

AU - Cooper, Matthew A

AU - Li, Jian

AU - Davis, T.P.

AU - Quinn, J.F.

AU - Velkov, T.

AU - Whittaker, M.R.

N1 - Export Date: 25 July 2016 CODEN: RSCAC Correspondence Address: Whittaker, M.R.; Australian Research Council, Centre of Excellence in Convergent Bio-Nano Science and Technology, 381 Royal Pde, Australia; email: michael.whittaker@monash.edu References: (2014) CDC-Get Smart: Know When Antibiotics Work 2013, , http://www.cdc.gov/getsmart/antibiotic-use/antibiotic-resistance-faqs.html#how-bacteria-resist, 17 April; Nolte, O., (2014) Protein Pept. Lett., 21, pp. 330-335; Rice, L.B., Challenges in identifying new antimicrobial agents effective for treating infections with Acinetobacter baumannii and Pseudomonas aeruginosa (2006) Clin. Infect. Dis., 43, pp. S100-S105; Chambers, H.F., (2001) Postgrad. Med., 109, pp. 43-50; Who, (2014) ANTIMICROBIAL RESISTANCE Global Report on Surveillance, , WHO Library; Ling, L.L., Schneider, T., Peoples, A.J., Spoering, A.L., Engels, I., Conlon, B.P., (2015) Nature, 517, pp. 455-459; Yeung, A.T.Y., Gellatly, S.L., Hancock, R.E.W., (2011) Cell. Mol. Life Sci., 68, pp. 2161-2176; Nederberg, F., Zhang, Y., Tan, J.P., Xu, K., Wang, H., Yang, C., (2011) Nat. Chem., 3, pp. 409-414; Locock, K.E.S., Michl, T.D., Valentin, J.D.P., Vasilev, K., Hayball, J.D., Qu, Y., (2013) Biomacromolecules, 14, pp. 4021-4031; Giuliani, A., Pirri, G., Nicoletto, S.F., (2007) Cent. Eur. J. Biol., 2, pp. 1-33; Kuroda, K., Caputo, G.A., (2013) Wiley Interdiscip. Rev.: Nanomed. Nanobiotechnol., 5, pp. 49-66; Kenawy, E.R., Worley, S.D., Broughton, R., (2007) Biomacromolecules, 8, pp. 1359-1384; Timofeeva, L., Kleshcheva, N., (2011) Appl. Microbiol. Biotechnol., 89, pp. 475-492; Mowery, B.P., Lindner, A.H., Weisblum, B., Stahl, S.S., Gellman, S.H., (2009) J. Am. Chem. Soc., 131, pp. 9735-9745; Michl, T.D., Locock, K.E.S., Stevens, N.E., Hayball, J.D., Vasilev, K., Postma, A., (2014) Polym. Chem., 5, pp. 5813-5822; Gody, G., Maschmeyer, T., Zetterlund, P.B., Perrier, S., (2013) Nat. Commun., 4, pp. 1-9; Anastasaki, A., Nikolaou, V., Nurumbetov, G., Wilson, P., Kempe, K., Quinn, J.F., Davis, T.P., Haddleton, D.M., (2015) Chem. Rev.; Boyer, C., Zetterlund, P.B., Whittaker, M.R., (2014) J. Polym. Sci., Part A: Polym. Chem., 52, pp. 2083-2098; Boyer, C., Soeriyadi, A.H., Zetterlund, P.B., Whittaker, M.R., (2011) Macromolecules, 44, pp. 8028-8033; Soeriyadi, A.H., Boyer, C., Nyström, F., Zetterlund, P.B., Whittaker, M.R., (2011) J. Am. Chem. Soc., 133, pp. 11128-11131; Lee, J., (2007), PhD thesis, University of North CarolinaMartin, T.P., (2007), PhD thesis, Massachusetts Institute of TechnologyRawlinson, L.A.B., Ryan, S.M., Mantovani, G., Syrett, J.A., Haddleton, D.M., Brayden, D.J., (2010) Biomacromolecules, 11, pp. 443-453; Zuo, H.J., Wu, D.C., Fu, R.W., (2010) Polym. J., 42, pp. 766-771; Lin, S., Wu, J.H., Jia, H.Q., Hao, L.M., Wang, R.Z., Qi, J.C., (2013) RSC Adv., 3, pp. 20758-20764; Dutta, P., Dey, J., Shome, A., Das, P.K., (2011) Int. J. Pharm., 414, pp. 298-311; Talbot, G.H., Bradley, J., Edwards, J.E., Gilbert, D., Scheld, M., Bartlett, J.G., (2006) Clin. Infect. Dis., 42, pp. 657-668; Boucher, H.W., Talbot, G.H., Bradley, J.S., Edwards, J.E., Gilbert, D., Rice, L.B., (2009) Clin. Infect. Dis., 48, pp. 1-12; Ciampolini, M., Nardi, N., (1966) Inorg. Chem., 5, pp. 41-44; Anderson, R.C., Hancock, R.E.W., Yu, P.L., (2004) Antimicrob. Agents Chemother., 48, pp. 673-676; Helander, I.M., Mattila-Sandholm, T., (2000) J. Appl. Microbiol., 88, pp. 213-219; Dathe, M., Wieprecht, T., (1999) Biochim. Biophys. Acta, Biomembr., 1462, pp. 71-87; Bütün, V., Armes, S.P., Billingham, N.C., (2001) Macromolecules, 34, pp. 1148-1159; Lu, G., Wu, D., Fu, R., (2007) React. Funct. Polym., 67, pp. 355-366; Tashiro, T., (2001) Macromol. Mater. Eng., 286, pp. 63-87; Li, J., Nation, R.L., Owen, R.J., Wong, S., Spelman, D., Franklin, C., (2007) Clin. Infect. Dis., 45, pp. 594-598; Nikaido, H., (2003) Microbiol. Mol. Biol. Rev., 67, pp. 593-656; Moffatt, J.H., Harper, M., Harrison, P., Hale, J.D.F., Vinogradov, E., Seemann, T., (2010) Antimicrob. Agents Chemother., 54, pp. 4971-4977; Zhang, L.J., Dhillon, P., Yan, H., Farmer, S., Hancock, R.E.W., (2000) Antimicrob. Agents Chemother., 44, pp. 3317-3321; Wang, Y., Zhou, Z., Zhu, J., Tang, Y., Canady, T.D., Chi, E.Y., (2011) Polymers, 3, pp. 1199-1214; Helander, I.M., Nurmiaho-Lassila, E.L., Ahvenainen, R., Rhoades, J., Roller, S., (2001) Int. J. Food Microbiol., 71, pp. 235-244; Johnson, L., Mulcahy, H., Kanevets, U., Shi, Y., Lewenza, S., (2012) J. Bacteriol., 194, pp. 813-826; Rubén, D.L., Tejero, D.L., López-Fabal, F., Gómez-Garcés, J.L., Fernández-García, M., (2015) Polym. Chem., 6, pp. 3449-3459; Punia, A., Mancuso, A., Banerjee, P., Yang, N.-L., (2015) ACS Macro Lett., 4, pp. 426-430; Palermo, E.F., Kuroda, K., (2010) Appl. Microbiol. Biotechnol., 87, pp. 1605-1615; Hwang, T.L., Aljuffali, I.A., Lin, C.F., Chang, Y.T., Fang, J.Y., (2015) Int. J. Nanomed., 10, pp. 371-385; Fischer, D., Li, Y.X., Ahlemeyer, B., Krieglstein, J., Kissel, T., (2003) Biomaterials, 24, pp. 1121-1131; Truong, N.P., Jia, Z.F., Burges, M., McMillan, N.A.J., Monteiro, M.J., (2011) Biomacromolecules, 12, pp. 1876-1882; Lv, H.T., Zhang, S.B., Wang, B., Cui, S.H., Yan, J., (2006) J. Controlled Release, 114, pp. 100-109; Shannahan, J.H., Lai, X.Y., Ke, P.C., Podila, R., Brown, J.M., Witzmann, F.A., (2013) PLoS One, 8, p. 10; Wang, F.J., Yu, L., Monopoli, M.P., Sandin, P., Mahon, E., Salvati, A., (2013) Nanomedicine, 9, pp. 1159-1168; Ilic, N., Novkovic, M., Guida, F., Xhindoli, D., Benincasa, M., Tossi, A., (2013) Biochim. Biophys. Acta, Biomembr., 1828, pp. 1004-1012; Li, Y.M., Bionda, N., Yongye, A., Geer, P., Stawikowski, M., Cudic, P., (2013) ChemMedChem, 8, pp. 1865-1872

PY - 2016

Y1 - 2016

N2 - The balance of cationicity and hydrophobicity can profoundly affect the performance of antimicrobial polymers. To this end a library of 24 cationic polymers with uniquely low degrees of polymerization was synthesized via Cu(0)-mediated polymerization, using three different cationic monomers and two initiators: providing two different hydrocarbon chain tail lengths (C2 and C12). The polymers exhibited structure-dependent antibacterial activity when tested against a selection of bacteria, viz., Staphylococcus aureus ATCC 29213, Klebsiella pneumoniae ATCC 13883, Acinetobacter baumannii ATCC 19606, and Pseudomonas aeruginosa ATCC 27853 as a representative palette of Gram-positive and Gram-negative ESKAPE pathogens. The five best-performing polymers were identified for additional testing against the polymyxin-resistant A. baumannii ATCC 19606R strain. Polymers having the lowest DP and a C12 hydrophobic tail were shown to provide the broadest antimicrobial activity against the bacteria panel studied as evidenced by lower minimum inhibitory concentrations (MICs). An optimal polymer composition was identified, and its mechanism of action investigated via membrane permeability testing against Escherichia coli. Membrane disruption was identified as the most probable mechanism for bacteria cell killing.

AB - The balance of cationicity and hydrophobicity can profoundly affect the performance of antimicrobial polymers. To this end a library of 24 cationic polymers with uniquely low degrees of polymerization was synthesized via Cu(0)-mediated polymerization, using three different cationic monomers and two initiators: providing two different hydrocarbon chain tail lengths (C2 and C12). The polymers exhibited structure-dependent antibacterial activity when tested against a selection of bacteria, viz., Staphylococcus aureus ATCC 29213, Klebsiella pneumoniae ATCC 13883, Acinetobacter baumannii ATCC 19606, and Pseudomonas aeruginosa ATCC 27853 as a representative palette of Gram-positive and Gram-negative ESKAPE pathogens. The five best-performing polymers were identified for additional testing against the polymyxin-resistant A. baumannii ATCC 19606R strain. Polymers having the lowest DP and a C12 hydrophobic tail were shown to provide the broadest antimicrobial activity against the bacteria panel studied as evidenced by lower minimum inhibitory concentrations (MICs). An optimal polymer composition was identified, and its mechanism of action investigated via membrane permeability testing against Escherichia coli. Membrane disruption was identified as the most probable mechanism for bacteria cell killing.

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U2 - 10.1039/c5ra24361k

DO - 10.1039/c5ra24361k

M3 - Article

VL - 6

SP - 15469

EP - 15477

JO - RSC Advances

JF - RSC Advances

SN - 2046-2069

IS - 19

ER -