Date of Award

8-27-2024

Document Type

Dissertation

Degree Name

Molecular Biosciences, Ph.D.

First Advisor

Mohammad Abrar Alam

Committee Members

Asela Wijeratne, David Gilmore, Jianfeng Xu, Sudeepa Bhattacharya

Call Number

LD 251 .A566d 2024 K39

Abstract

In recent years, the rise of antibiotic-resistant bacteria has become a global concern, resulting in fewer effective antibiotics. Several conventional antibacterial agents are ineffective against these, necessitating novel molecules with enhanced efficacy and diverse actions. We developed pyrazole and thiazole-based antibacterial agents and demonstrated that they have significant potency (minimum inhibitory concentration as low as 0.39 µg/mL) against antibiotic-resistant and susceptible bacteria, as well as promising anti-biofilm and anti-persister activity. In vivo toxicity tests on Caenorhabditis elegans showed no significant harm to this model host organism at low compound concentrations. These compounds rescued C. elegans from methicillin-resistant Staphylococcus aureus (MRSA) infection and death. Investigations into the mode of action of these compounds against MRSA showed disruption of cell membrane integrity and damage to the bacterial cell wall, validated through various assays. Future research will aim to investigate their efficacy in mice and explore additional modes of action. Overall, our findings indicate the compounds' potent activity against drug-resistant bacteria, non-toxicity in a nematode model, effective rescue of nematodes from MRSA infection, cell wall and cell membrane targeting as the mode of action and show promising potential for further study in antibiotic development.

Rights Management

Creative Commons Attribution-NonCommercial 4.0 International License
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License

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