TY - JOUR
T1 - Tuning the biological activity profile of antibacterial polymers via subunit substitution pattern
AU - Liu, Runhui
AU - Chen, Xinyu
AU - Chakraborty, Saswata
AU - Lemke, Justin J.
AU - Hayouka, Zvi
AU - Chow, Clara
AU - Welch, Rodney A.
AU - Weisblum, Bernard
AU - Masters, Kristyn S.
AU - Gellman, Samuel H.
PY - 2014/3/19
Y1 - 2014/3/19
N2 - Binary nylon-3 copolymers containing cationic and hydrophobic subunits can mimic the biological properties of host-defense peptides, but relationships between composition and activity are not yet well understood for these materials. Hydrophobic subunits in previously studied examples have been limited mostly to cycloalkane-derived structures, with cyclohexyl proving to be particularly promising. The present study evaluates alternative hydrophobic subunits that are isomeric or nearly isomeric with the cyclohexyl example; each has four sp3 carbons in the side chains. The results show that varying the substitution pattern of the hydrophobic subunit leads to relatively small changes in antibacterial activity but causes significant changes in hemolytic activity. We hypothesize that these differences in biological activity profile arise, at least in part, from variations among the conformational propensities of the hydrophobic subunits. The α,α,β,β- tetramethyl unit is optimal among the subunits we have examined, providing copolymers with potent antibacterial activity and excellent prokaryote vs eukaryote selectivity. Bacteria do not readily develop resistance to the new antibacterial nylon-3 copolymers. These findings suggest that variation in subunit conformational properties could be generally valuable in the development of synthetic polymers for biological applications.
AB - Binary nylon-3 copolymers containing cationic and hydrophobic subunits can mimic the biological properties of host-defense peptides, but relationships between composition and activity are not yet well understood for these materials. Hydrophobic subunits in previously studied examples have been limited mostly to cycloalkane-derived structures, with cyclohexyl proving to be particularly promising. The present study evaluates alternative hydrophobic subunits that are isomeric or nearly isomeric with the cyclohexyl example; each has four sp3 carbons in the side chains. The results show that varying the substitution pattern of the hydrophobic subunit leads to relatively small changes in antibacterial activity but causes significant changes in hemolytic activity. We hypothesize that these differences in biological activity profile arise, at least in part, from variations among the conformational propensities of the hydrophobic subunits. The α,α,β,β- tetramethyl unit is optimal among the subunits we have examined, providing copolymers with potent antibacterial activity and excellent prokaryote vs eukaryote selectivity. Bacteria do not readily develop resistance to the new antibacterial nylon-3 copolymers. These findings suggest that variation in subunit conformational properties could be generally valuable in the development of synthetic polymers for biological applications.
UR - http://www.scopus.com/inward/record.url?scp=84896501256&partnerID=8YFLogxK
U2 - 10.1021/ja500367u
DO - 10.1021/ja500367u
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C2 - 24601599
AN - SCOPUS:84896501256
SN - 0002-7863
VL - 136
SP - 4410
EP - 4418
JO - Journal of the American Chemical Society
JF - Journal of the American Chemical Society
IS - 11
ER -