Antimicrobial cationic polycarbonates
Antimicrobial cationic polymers having one or two cationic polycarbonate chains were prepared by organocatalyzed ring opening polymerization. One antimicrobial cationic polymer has a polymer chain consisting essentially of cationic carbonate repeat units linked to one or two end groups. The end groups can comprise a covalently bound form of biologically active compound such as cholesterol. Other antimicrobial cationic polymers have a random copolycarbonate chain comprising a minor mole fraction of hydrophobic repeat units bearing a covalently bound form of a vitamin E and/or vitamin D2. The cationic polymers exhibit high activity and selectivity against Gram-negative and Gram-positive microbes and fungi.
1. An antimicrobial cationic polymer of formula (12):
Z c —P b —C—P b —Z c (12),
wherein
C′ is a C 2 -C 15 divalent linking group joining polymer chains P b , wherein C′ comprises i) a first heteroatom linked to a first polymer chain P b , wherein the first heteroatom is selected from the group consisting of nitrogen, oxygen, and sulfur, and ii) a second heteroatom linked to a second polymer chain P b , wherein the second heteroatom is selected from the group consisting of nitrogen, oxygen, and sulfur,
each Z c is an independent monovalent end group selected from the group consisting of hydrogen and C 1 -C 15 moieties,
each polymer chain P b consists essentially of cationic carbonate repeat units, wherein i) the cationic polymer comprises a total of 5 to about 45 cationic carbonate repeat units, ii) each of the cationic carbonate repeat units comprises a) a backbone portion of the polymer chain comprising an aliphatic carbonate group, and b) a cationic side chain linked to the backbone portion, and iii) the cationic side chain comprises a positive-charged heteroatom Q′ of a quaternary ammonium group and/or quaternary phosphonium group,
about 25% to 100% of all the cationic carbonate repeat units of the cationic polymer, designated first cationic carbonate repeat units, having a structure selected from the group consisting of
and combinations thereof, wherein X − is a negative-charged ion, and
0% to about 75% of the cationic carbonate repeat units of the cationic polymer, designated second cationic carbonate repeat units, have a cationic side chain comprising 6 to 9 carbons.
2. The cationic polymer of claim 1 , wherein the second cationic carbonate repeat units have a cationic side chain comprising 6 to 12 carbons.
3. The cationic polymer of claim 1 , wherein the first cationic repeat units have the structure
4. The cationic polymer of claim 1 , wherein the first cationic repeat units have the structure
5. The cationic polymer of claim 1 , wherein the first cationic carbonate repeat units have the structure
6. The cationic polymer of claim 1 , wherein the first cationic repeat units have the structure
7. The cationic polymer of claim 1 , wherein the cationic polymer is effective in killing a microbe selected from the group consisting of Staphylococcus epidermidis ( S. epidermidis ), Staphylococcus aureus ( S. aureus ), Escherichia coli ( E. coli ), Pseudomonas aeruginosa ( P. aeruginosa ), Candida albicans ( C. albicans ), Methicillin-resistant Staphylococcus aureus (MRSA), Vancomycin-resistant Enterococcus (VRE), Acinetobacter baumannii ( A. baumannii ), Cryptococcus neoformans ( C. neoformans ), Klebsiella pneumoniae ( K. pneumoniae ), and combinations thereof.
8. An antimicrobial cationic polymer of formula (14):
Z c —P b —C″—P b —Z c (14),
wherein
C″ is a divalent linking group joining polymer chains P b , wherein C″ comprises i) a first heteroatom linked to a first polymer chain P b , wherein the first heteroatom is selected from the group consisting of nitrogen, oxygen, and sulfur, ii) a second heteroatom linked to a second polymer chain P b , wherein the second heteroatom is selected from the group consisting of nitrogen, oxygen, and sulfur, and iii) a covalently bound form of a compound selected from the group consisting of steroids, non-steroid hormones, vitamins, and drugs,
each Z′ is an independent monovalent end group selected from the group consisting of hydrogen and C 1 -C 15 moieties,
each polymer chain P b consists essentially of cationic carbonate repeat units, wherein i) the cationic polymer comprises a total of 5 to about 45 cationic carbonate repeat units, ii) each of the cationic carbonate repeat units comprises a) a backbone portion of the polymer chain comprising an aliphatic carbonate group, and b) a C 6 -C 25 cationic side chain linked to the backbone portion, and iii) the cationic side chain comprises a positive-charged heteroatom Q′ of a quaternary ammonium group and/or quaternary phosphonium group,
about 25% to 100% of the cationic carbonate repeat units of the cationic polymer, designated first cationic carbonate repeat units, having a structure selected from the group consisting of
and combinations thereof, wherein X − is a negative-charged ion, and
0% to about 75% of the cationic carbonate repeat units of the cationic polymer,
designated second cationic carbonate repeat units, have a cationic side chain group comprising 6 to 9 carbons.
9. The cationic polymer of claim 8 , wherein C″ comprises a cholesteryl group.
10. The cationic polymer of claim 8 , wherein C″ comprises a covalently bound form of vitamin.
11. The cationic polymer of claim 8 , wherein the vitamin is selected from the group consisting of vitamin E compounds, vitamin D compounds, and combinations thereof.
12. An antimicrobial cationic random copolymer of formula (16):
Z c —P c —C′—P c —Z c (16),
wherein
C′ is a C 2 -C 15 divalent linking group joining polymer chains P c , wherein C′ comprises i) a first heteroatom linked to a first polymer chain P c , wherein the first heteroatom is selected from the group consisting of nitrogen, oxygen, and sulfur, and ii) a second heteroatom linked to a second polymer chain P c , wherein the second heteroatom is selected from the group consisting of nitrogen, oxygen, and sulfur,
each Z c is an independent monovalent end group selected from the group consisting of hydrogen and C 1 -C 15 moieties,
each P c is a polymer chain consisting essentially of I) about 85 mol % to 99.9 mol % of cationic carbonate repeat units, and II) 0.1 mol % to about 15 mol % of a carbonate repeat unit comprising a covalently bound form of a steroid and/or a vitamin compound, designated H′, wherein i) the cationic polymer has a total number of repeat units of about 5 to about 45, ii) each of the cationic carbonate repeat units comprises a) a polymer backbone portion comprising an aliphatic carbonate group, and b) a C 6 -C 25 cationic side chain portion linked to the polymer backbone portion, and iii) each cationic side chain portion comprises a positive-charged heteroatom Q′ of a quaternary ammonium group and/or quaternary phosphonium group,
about 25% to 100% of the cationic carbonate repeat units of the cationic polymer, designated first cationic carbonate repeat units, having a structure selected from the group consisting of
and combinations thereof, wherein X − is a negative-charged ion, and
0% to about 75% of the cationic carbonate repeat units of the cationic polymer,
designated second cationic carbonate repeat units, have a cationic side chain group comprising 6 to 9 carbons.
13. The random copolymer of claim 12 , wherein H′ is a covalently bound form of alpha-tocopherol.
14. The random copolymer of claim 12 , wherein H′ is a covalently bound form of ergocalciferol.
15. An antimicrobial cationic polymer has a structure in accordance with formula (18):
Y c —P b —C′—P b —Y d (18),
wherein
C′ is a C 2 -C 15 divalent linking group joining polymer chains P b , wherein C′ comprises i) a first heteroatom linked to a first polymer chain P b , wherein the first heteroatom is selected from the group consisting of nitrogen, oxygen, and sulfur, and ii) a second heteroatom linked to a second polymer chain P b , wherein the second heteroatom is selected from the group consisting of nitrogen, oxygen, and sulfur,
Y c is an independent monovalent first end group selected from the group consisting of hydrogen, groups comprising a covalently bound form of a steroid, and groups comprising a covalently bound form of a vitamin,
Y d is an independent monovalent second end group selected from the group consisting of hydrogen, groups comprising a covalently bound form of a steroid, and groups comprising a covalently bound form of a vitamin,
each polymer chain P b consists essentially of cationic carbonate repeat units, wherein i) the cationic polymer comprises a total of 5 to about 45 cationic carbonate repeat units, ii) each of the cationic carbonate repeat units comprises a) a backbone portion of the polymer chain comprising an aliphatic carbonate group, and b) a cationic side chain linked to the backbone portion, and iii) the cationic side chain comprises a positive-charged heteroatom Q′ of a quaternary ammonium group and/or quaternary phosphonium group,
about 25% to 100% of all the cationic carbonate repeat units of the cationic polymer, designated first cationic carbonate repeat units, having a structure selected from the group consisting of
and combinations thereof, wherein X − is a negative-charged ion, and
0% to about 75% of the cationic carbonate repeat units of the cationic polymer, designated second cationic carbonate repeat units, have a cationic side chain comprising 6 to 9 carbons.
16. An aqueous composition for killing a microbe comprising the cationic polymer of claim 1 .
17. The composition of claim 16 , wherein the composition can be administered by injection.
18. The composition of claim 16 , wherein the cationic polymer has a critical micelle concentration, and the concentration of the cationic polymer is below the critical micelle concentration of the cationic polymer.
19. A method of killing a microbe, comprising contacting the microbe with the cationic polymer of claim 1 .
20. A method of forming the cationic polymer of claim 8 , comprising,
forming a polycarbonate by an organocatalyzed ring opening polymerization (ROP) of a cyclic carbonate monomer, wherein the ROP is initiated by a di-nucleophilic compound selected from the group consisting of steroids, vitamins, compounds comprising a covalently bound form of the foregoing steroids and vitamins, and combinations thereof;
optionally endcapping the polycarbonate; and
treating the polycarbonate with a quaternizing agent, thereby forming the cationic polymer,
wherein the cyclic carbonate monomer has a structure selected from the group consisting of
and combinations thereof.
21. The method of claim 20 , wherein the quaternizing agent is a tertiary amine selected from the group consisting of N-butylimidazole, trimethylamine, dimethylbenzylamine, dimethylbutylamine, and combinations thereof.
22. The method of claim 20 , wherein the quaternizing agent is dimethylbenzylamine.
23. The method of claim 20 , wherein the initiator is Chol-MPA: