# Design of Poly-Catechol Biodynamers for Potentiation of Antibiotic Efficacy against Drug-Resistant Bacteria

## TL;DR

This paper introduces a new water-soluble polymer that boosts antibiotic effectiveness against drug-resistant bacteria by generating reactive oxygen species.

## Contribution

A novel biodynamer with high catechol content and pH-responsive degradation is developed to enhance antibiotic efficacy.

## Key findings

- DOPA-BD releases 3-fold more DOPA-hydrazide under acidic infection conditions.
- The polymer synergistically enhances Azithromycin's efficacy 4-fold against resistant E. coli.
- DOPA-BD remains stable for 72 hours in physiological buffer and induces ROS production in bacteria.

## Abstract

Catechol-modified polymers, such as DOPA-functionalized
systems,
have recently gained significant interest for a variety of biomedical
applications, particularly in their role as antibacterial adjuvants
due to their oxidative activity and ability to generate reactive oxygen
species (ROS). Current catechol-functionalized polymers, however,
often suffer from a restricted number of catechol groups, limited
biocompatibility and solubility, and low stability due to the rapid
oxidation under physiological conditions. In this study, we developed
a water-soluble, biocompatible DOPA-modified biodynamer (DOPA-BD),
leveraging the principles of constitutional dynamic chemistry (CDC).
DOPA-BD was synthesized via polycondensation of DOPA-hydrazide and
the hexaethylene glycol-conjugated carbazole dialdehyde (CA-HG), forming
dynamic imine and acylhydrazone linkages between the monomers. As
a result of its dynamic covalent backbone, DOPA-BD exhibits biodegradability
and undergoes pH-responsive degradation under mildly acidic conditions
typically found at infection sites, leading to a more than 3-fold
increase in DOPA-hydrazide release compared to physiological pH. Interestingly,
driven by CDC, DOPA-BD folds into a nanorod structure with a hydrodynamic
diameter of ∼7.8 nm, surrounded by HG chains that offer water
solubility and biocompatibility. Moreover, the incorporation of the
DOPA-derivative in each repeating unit yields a polymer with exceptionally
high catechol content, which remains stable and resistant to oxidation
for 72 h in physiological buffer conditions. Regarding its antibacterial
applicability, DOPA-BD demonstrated synergistic antibacterial activity
with Azithromycin (AZM) against AZM-resistant E. coli, enhancing the antibiotic’s efficacy by 4-fold. Our study
indicates that DOPA-BD induces ROS production in the respective bacterial
strain, suggesting ROS generation as one of the possible mechanisms
contributing to the observed synergy. Overall, DOPA-BD represents
a promising alternative strategy to potentiate antibacterial activity
against resistant strains, holding strong potential for future antibacterial
applications.