Doctor of Philosophy (PhD)
First Advisor's Name
Joong Ho Moon
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antimicrobial polymers, antimycobacterial polymers, guanylurea, carbomoylated guanidine, proton motive force, mycobacteria
Date of Defense
Tuberculosis (TB) continues to be a serious threat worldwide, especially in developing countries. Current first-line treatment for TB infections is a multidrug regimen for 4-9 months; if not taken as prescribed, drug-resistant TB can emerge. Novel drugs with unconventional targets are warranted to lessen the lengthy and four-drug treatment. Antimicrobial polymers mimicking naturally occurring antimicrobial peptides (AMPs) have gained much attention due to their enzymatic stability, tunability, cost-effectiveness, and unique mode of action - directly or indirectly - on bacterial membrane. However, selectivity and toxicity have limited their biological applications. Previously, our group synthesized a novel class of antimicrobial polymers, poly(guanylurea)s (PGUs). Unlike conventional AMP-mimics, poly (guanylurea piperazine)s have a linear architecture (i.e., no pendants) with all key functional groups along the backbone, resulting in low cytotoxicity and selectivity against mycobacteria. Here, this work explores the inherent antimycobacterial selectivity and bactericidal activity of PGU-P-8K on M. smegmatis, as a model organism for mycobacteria. PGU-P-8K showed fast-acting bactericidal activity (i.e., less than a day) at its minimum bactericidal concentration (MBC). This effect was further explored and attributed it to PGU-P-8K interfering with the bioenergetics in mycobacteria. PGU-P-8K displayed targeting the mycobacterial cell envelope by disrupting multiple intracellular processes while retaining the cell membrane integrity, confirmed by imagining of post-treatment cells and overexpression of genes related to cell envelope stress. Additionally, this project investigates how the key functionalities (e.g., aromatic substituents, amphiphilicity, rigidity) along the backbone of PGU-P-8K play a role in its antimycobacterial activity. The in-depth studies of how the physicochemical properties of PGU-P-8K affect selectivity and mode of action on mycobacteria contributes to the development of a novel class of membrane targeting drugs or drug adjuvants for improving TB treatment.
Miranda, Michelle M., "Synthesis, Structure-Activity and Mechanism Studies of Poly(guanylurea)s against Mycobacteria" (2022). FIU Electronic Theses and Dissertations. 5026.
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