Graduation Year

2023

Document Type

Dissertation

Degree

Ph.D.

Degree Name

Doctor of Philosophy (Ph.D.)

Degree Granting Department

Chemistry

Major Professor

Jianfeng Cai, Ph.D.

Committee Member

Feng Cheng, Ph.D.

Committee Member

Kirpal Bisht, Ph.D.

Committee Member

Wenqi Liu, Ph.D.

Keywords

antimicrobial resistance, Clostridioides difficile, Guanidium, Amphiphilic polymers

Abstract

The World Health Organization (WHO) has identified the emergence of antibiotic resistance as one of the top 10 threats to public health. This is exemplified by serious threats such as methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus faecalis (VREF), and the urgent threat posed by Clostridioides difficile to human health. As part of a multifaceted combat strategy against these pathogenic bacteria, host-defense peptide (HDP)-mimicking polymers have proven to be resourceful and promising. However, a vast majority of antibiotic polymer applications were limited to topical applications due to their potential systematic toxicity. Herein, we report the design and synthesis of a series of novel biodegradable polymers – the lipidated antimicrobial guanidinylate polycarbonates. These novel polymers exhibit potent antimicrobial efficacy against both Gram-negative and Gram-positive bacteria, displaying rapid kinetic killing ability and a diminished propensity for resistance development. The bacterial killing process was found to be due to bacterial membrane disruptions, akin to the action mode of HDPs. Importantly, the optimal polymer showed significant antibacterial activity against C. difficile infection (CDI) in vivo through oral administration. In comparison to vancomycin, the standard CDI treatment, the synthesized polymer exhibits a prolonged therapeutic effect and notably reduces CDI recurrence rate. The convenient synthesis, easy scale-up, low cost, as well biodegradability of this class of polycarbonates, together with their in vitro antimicrobial activity and orally in vivo activity against CDI, suggested the great potential of lipidated guandinylate polycarbonates as a new class of antibacterial biomaterials to treat CDI and combat emerging antibiotic resistance. The length of the lipid tail has been modulated to achieve broad-spectrum activity while minimizing hemolytic effects. Moreover, we explored the synergistic potential of using N-Acetyl cysteine (NAC) in conjunction with lipidated guanidinylate polycarbonates. This combination has exhibited enhanced bacterial clearance and improved treatment efficacy, as well as potentiated the activity of the lipidated guanidinylate polycarbonates against both Gram-positive and Gram-negative bacteria, including resistant strains. The amalgamation of NAC and lipidated guanidinylate polycarbonates has also been proven efficacious in inhibiting biofilm formation. Results suggest the combination treatment of NAC and the lipidated guanidinylate polycarbonates may lead to the development of a novel class of antimicrobial agents.

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