Synthesis of Antimicrobial Polymers to Overcome Antimicrobial Resistance

Authors

Md Salauddin Ahmed, Florida International UniversityFollow

Document Type

Dissertation

Degree

Doctor of Philosophy (PhD)

Major/Program

Chemistry

First Advisor's Name

Joong ho Moon

First Advisor's Committee Title

Committee chair

Second Advisor's Name

Kevin O’Shea

Second Advisor's Committee Title

Committee member

Third Advisor's Name

Yukching Tse Dinh

Third Advisor's Committee Title

Committee member

Fourth Advisor's Name

Kalai Mathee

Fourth Advisor's Committee Title

Committee member

Fifth Advisor's Name

Watson Lees

Fifth Advisor's Committee Title

Committee member

Keywords

Antimicrobial, Polymer, Poly(guanylurea), Amidinourea, Resistance, Conjugated polymer, Gene delivery

Date of Defense

12-6-2017

Abstract

Drug-resistant pathogens are emerging rapidly and thwart the treatment of common bacterial infectious diseases that can lead to death. Many contagious diseases remain difficult to treat because of acquired drug resistance. Compared to small antibiotics, which interrupt the intracellular biochemical processes, antimicrobial polymers with relatively high molecular weights offer a promising strategy to overcome drug resistance by disrupting the physical integrity of the membrane. Because of the unique mechanism, bacteria need a much longer time to develop resistance.

A new class of antimicrobial polymer in which the positive charge and hydrophobic/hydrophilic units are linearly connected in the amidinourea backbone was designed, synthesized, and tested for various bacteria including methicillin-resistant Staphylococcus aureus (MRSA). We evaluated the effects of hydrophobicity and polymer molecular weights on antimicrobial activity by measuring minimum inhibitory concentrations (MIC) and hemolytic activities (HC₅₀). Amidinourea antimicrobial polymers exhibit a promising MIC₉₀ value (13 μg/mL) with low HC₅₀, resulting in high selectivity (HC₅₀/MIC₉₀) against MRSA.

Many bacteria have developed resistance against Ciprofloxacin. To overcome the antibiotic resistance associated with Ciprofloxacin, we hypothesized that a steady release of Ciprofloxacin at the bacteria membrane can overcome the drug resistance because the local drug concentration can be overwhelmingly high to suppress the drug efflux pump expressed on the membrane. A series of homo and di-block copolymers containing Ciprofloxacin, as the form of prodrugs, was synthesized using ring-opening metathesis polymerization (ROMP), and we evaluated their antimicrobial efficacy.While homo polymers only containing Ciprofloxacin were inactive against almost all bacteria tested, di-block copolymers containing Cipro and triphenylphosphine exhibited some antimicrobial activity against wild type M. smegmatis.

Modulation of chemical environments at the positively charged polymeric materials can significantly influence the biophysical properties required for efficient cellular interaction and subsequent entry. Using intrinsic fluorescent conjugated polymers (CPs), we have demonstrated that the modulated guanidine group with various hydrophilic or hydrophobic moieties dramatically changed their cellular behaviors. We prepared a series of modified guanidine-containing CPs and examined their cellular behaviors by using confocal microscopic imaging. Details of the modification chemistry and modification-dependent cellular behaviors and a knockdown of a target protein in primary cells were discussed.

Identifier

FIDC006577

Creative Commons License

This work is licensed under a Creative Commons Attribution 4.0 License.

Recommended Citation

Ahmed, Md Salauddin, "Synthesis of Antimicrobial Polymers to Overcome Antimicrobial Resistance" (2017). FIU Electronic Theses and Dissertations. 3692.
https://digitalcommons.fiu.edu/etd/3692