Synthesis, Structure-Activity and Mechanism Studies of Poly(guanylurea)s against Mycobacteria

Authors

Michelle M. Miranda, 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

Yuk-Ching Tse-Dinh

Second Advisor's Committee Title

committee member

Third Advisor's Name

Kevin O’Shea

Third Advisor's Committee Title

committee member

Fourth Advisor's Name

Christopher Dares

Fourth Advisor's Committee Title

committee member

Fifth Advisor's Name

Kalai Mathee

Fifth Advisor's Committee Title

committee member

Keywords

antimicrobial polymers, antimycobacterial polymers, guanylurea, carbomoylated guanidine, proton motive force, mycobacteria

Date of Defense

6-21-2022

Abstract

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.

Identifier

FIDC010756

ORCID

0000-0003-2718-8835

Recommended Citation

Miranda, Michelle M., "Synthesis, Structure-Activity and Mechanism Studies of Poly(guanylurea)s against Mycobacteria" (2022). FIU Electronic Theses and Dissertations. 5026.
https://digitalcommons.fiu.edu/etd/5026