Structure-activity relationships in self-immolative and photodynamic antibacterial polymers
Authors
Ergene, Cansu
ORCID
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Other Contributors
Palermo, Edmund
Ozisik, Rahmi
Ullal, Chaitanya
Lee, Sangwoo
Ozisik, Rahmi
Ullal, Chaitanya
Lee, Sangwoo
Issue Date
2019-05
Keywords
Materials science
Degree
PhD
Terms of Use
Attribution-NonCommercial-NoDerivs 3.0 United States
This electronic version is a licensed copy owned by Rensselaer Polytechnic Institute, Troy, NY. Copyright of original work retained by author.
This electronic version is a licensed copy owned by Rensselaer Polytechnic Institute, Troy, NY. Copyright of original work retained by author.
Full Citation
Abstract
We also developed silyl ether-capped PBE gels containing cationic or PEG units in side chains using PEG thiol crosslinkers via photoactivated thiol-ene click reaction. These gels maintained the self-immolation ability of PBE when exposed to fluoride in DMF, whereas they failed to decompose into monomer in methanol. With increasing PEG length in crosslinker, PBE gels also swell in water. However, resulting hydrogels did not degrade in aqueous conditions due to the presence of protons in water which re-caps the decapped chain ends.
Finally, we synthesized a set of oligo(thiophene)s with precisely controlled chain length, regioregularity, sequence and pendant side units via iterative convergent/divergent organometallic couplings. In addition to cationic and facially amphiphilic features, oligo(thiophene)s exerted a photodynamic mechanism of action. In the absence of light, they induce broad-spectrum and rapid bactericidal activity in micromolar range as HDPs. In contrast, antibacterial activity significantly increased by orders of magnitude upon the illumination of light, while not affecting the hemolytic activity. Potent antibacterial efficacy of thiophenes is linked to double mechanism of action: combination of bacterial cell binding and production of reactive oxygen species (ROS). Comonomer sequence and chain length showed a big impact on biological performance of compounds. To emphasize, the best candidate exhibited 1300-fold cell type-selectivity index. Furthermore, same compound showed orders of magnitude higher Escherichia coli killing activity than cytotoxicity against HeLa cell without inducing any bacterial resistance in 21 sub-inhibitory trials.
The high hemolytic activity of cationic PBEs is associated with the high hydrophobicity of polymer backbone. In next stage, we substituted neutral, hydrophilic PEG grafts in side chains in order to reduce to overall hydrophobicity of cationic homopolymers. The molar fraction of the statistical copolymers was adjusted to 0% to 100% PEG in side chains with varying the PEG length. The biological activity of copolymers was reported in terms of copolymer composition. Copolymers having 25-50% PEG-800 showed potent antibacterial efficacy, while hemolytic activity decreased with increasing PEG content. The best cell-type selectivity was exhibited by the copolymer bearing 50% primary ammonium and 50% PEG side chains, 56-fold higher compared to cationic homopolymer.
The rising number of infections related to antibiotic-resistance bacteria, in parallel to the decline in the development of new antibiotics, has emerged as a global health crisis. Host defense peptides (HDPs) are antimicrobial compounds as alternative to antibiotics that kill pathogens without inducing bacterial resistance and harming host cells. Since 2000’s, there is an interest to develop synthetic polymers that mimic the physiochemical features of HDPs with affordable largescale manufacturing cost. Self-immolative polymers (SIMPs) are a novel class of materials that can spontaneously depolymerize into monomers in response to a specific triggering event. In this dissertation, we present the first generation of antibacterial self-immolative polymers with potent, rapid and broad-range antibacterial efficacy. Biological performance of macromolecules were evaluated based on cationic functionality in side chains. Polymers with primary ammonium groups exhibited the most potent antibacterial activity relative to its tertiary and quaternary ammonium analogues. Interestingly, polymers bearing quaternary ammonium showed the lowest hemolysis whereas primary and tertiary amine functionalized PBEs were highly toxic to red blood cells (RBCs). In this study, PBEs with silyl ether end-caps and pendant allyl side units were modified with cationic substitutes via photoinitiated thiol-ene click chemistry. Self-immolative polycations retained their inherent degradation behavior upon side chain modification when exposed to fluoride ions in solution. Upon depolymerization, small products also possessed potent antibacterial activity as intact polymer, yet substantially reduced the hemolytic activity.
Finally, we synthesized a set of oligo(thiophene)s with precisely controlled chain length, regioregularity, sequence and pendant side units via iterative convergent/divergent organometallic couplings. In addition to cationic and facially amphiphilic features, oligo(thiophene)s exerted a photodynamic mechanism of action. In the absence of light, they induce broad-spectrum and rapid bactericidal activity in micromolar range as HDPs. In contrast, antibacterial activity significantly increased by orders of magnitude upon the illumination of light, while not affecting the hemolytic activity. Potent antibacterial efficacy of thiophenes is linked to double mechanism of action: combination of bacterial cell binding and production of reactive oxygen species (ROS). Comonomer sequence and chain length showed a big impact on biological performance of compounds. To emphasize, the best candidate exhibited 1300-fold cell type-selectivity index. Furthermore, same compound showed orders of magnitude higher Escherichia coli killing activity than cytotoxicity against HeLa cell without inducing any bacterial resistance in 21 sub-inhibitory trials.
The high hemolytic activity of cationic PBEs is associated with the high hydrophobicity of polymer backbone. In next stage, we substituted neutral, hydrophilic PEG grafts in side chains in order to reduce to overall hydrophobicity of cationic homopolymers. The molar fraction of the statistical copolymers was adjusted to 0% to 100% PEG in side chains with varying the PEG length. The biological activity of copolymers was reported in terms of copolymer composition. Copolymers having 25-50% PEG-800 showed potent antibacterial efficacy, while hemolytic activity decreased with increasing PEG content. The best cell-type selectivity was exhibited by the copolymer bearing 50% primary ammonium and 50% PEG side chains, 56-fold higher compared to cationic homopolymer.
The rising number of infections related to antibiotic-resistance bacteria, in parallel to the decline in the development of new antibiotics, has emerged as a global health crisis. Host defense peptides (HDPs) are antimicrobial compounds as alternative to antibiotics that kill pathogens without inducing bacterial resistance and harming host cells. Since 2000’s, there is an interest to develop synthetic polymers that mimic the physiochemical features of HDPs with affordable largescale manufacturing cost. Self-immolative polymers (SIMPs) are a novel class of materials that can spontaneously depolymerize into monomers in response to a specific triggering event. In this dissertation, we present the first generation of antibacterial self-immolative polymers with potent, rapid and broad-range antibacterial efficacy. Biological performance of macromolecules were evaluated based on cationic functionality in side chains. Polymers with primary ammonium groups exhibited the most potent antibacterial activity relative to its tertiary and quaternary ammonium analogues. Interestingly, polymers bearing quaternary ammonium showed the lowest hemolysis whereas primary and tertiary amine functionalized PBEs were highly toxic to red blood cells (RBCs). In this study, PBEs with silyl ether end-caps and pendant allyl side units were modified with cationic substitutes via photoinitiated thiol-ene click chemistry. Self-immolative polycations retained their inherent degradation behavior upon side chain modification when exposed to fluoride ions in solution. Upon depolymerization, small products also possessed potent antibacterial activity as intact polymer, yet substantially reduced the hemolytic activity.
Description
May 2019
School of Engineering
School of Engineering
Department
Dept. of Materials Science and Engineering
Publisher
Rensselaer Polytechnic Institute, Troy, NY
Relationships
Rensselaer Theses and Dissertations Online Collection
Access
CC BY-NC-ND. Users may download and share copies with attribution in accordance with a Creative Commons Attribution-Noncommercial-No Derivative Works 3.0 License. No commercial use or derivatives are permitted without the explicit approval of the author.