Please use this identifier to cite or link to this item: http://lib.jncasr.ac.in:8080/jspui/handle/10572/2300
Title: Isosteric substitution in cationic-amphiphilic polymers reveals an important role for hydrogen bonding in bacterial membrane interactions
Authors: Uppu, D. S. S. M.
Konai, M. M.
Baul, U.
Singh, P.
Siersma, T. K.
Samaddar, S.
Vemparala, S.
Hamoen, L. W.
Narayana, Chandrabhas
Haldar, Jayanta
Keywords: Chemistry
Antimicrobial Peptide Action
Molecular-Dynamics
Force-Field
Pore Formation
Antibacterial
Oligomers
Proteins
Binding
Amide
Acid
Issue Date: 2016
Publisher: Royal Society of Chemistry
Citation: Uppu, Dssm; Konai, M. M.; Baul, U.; Singh, P.; Siersma, T. K.; Samaddar, S.; Vemparala, S.; Hamoen, L. W.; Narayana, C.; Haldar, J., Isosteric substitution in cationic-amphiphilic polymers reveals an important role for hydrogen bonding in bacterial membrane interactions. Chemical Science 2016, 7 (7), 4613-4623 http://dx.doi.org/10.1039/c6sc00615a
Chemical Science
7
7
Abstract: Biomimetic antibacterial polymers, the functional mimics of antimicrobial peptides (AMPs), targeting the bacterial cell membrane have been developed to combat the problem of antibiotic resistance. Amphiphilicity, a balance of cationic charge and hydrophobicity, in these polymers has been shown to be pivotal for their selective interactions with anionic lipid membranes of bacteria instead of zwitterionic mammalian (human erythrocyte) membranes. However, it is unclear if and to what extent hydrogen bonding in amphiphilic antibacterial polymers contributes to this membrane binding specificity. To address this, we employ isosteric substitution of ester with amide moieties that differ in their potency for hydrogen bonding in the side chains of N-alkyl maleimide based amphiphilic polymers. Our studies reveal that amide polymer (AC3P) is a potent antibacterial agent with high membrane-disrupting properties compared to its ester counterpart (EC3P). To understand these differences we performed bio-physical experiments and molecular dynamics (MD) simulations which showed strong interactions of AC3P including hydrogen bonding with lipid head groups of bacterial model lipid bilayers, that are absent in EC3P, make them selective for bacterial membranes. Mechanistic investigations of these polymers in bacteria revealed specific membrane disruptive activity leading to the delocalization of cell division related proteins. This unprecedented and unique concept provides an understanding of bacterial membrane interactions highlighting the role of hydrogen bonding. Thus, these findings will have significant implications in efficient design of potent membrane-active agents.
Description: Open Access
URI: http://hdl.handle.net/10572/2300
ISSN: 2041-6520
Appears in Collections:Research Articles (Chandrabhas N.)
Research Papers (Jayanta Haldar)

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