# Stimuli-Responsive Polymer-Drug Conjugates: A New Strategy to Fight Antimicrobial Resistance

> **NIH NIH R21** · UNIVERSITY OF WISCONSIN-MADISON · 2021 · $191,661

## Abstract

PROJECT SUMMARY
Infectious diseases are a growing threat to public health owing to increasing antimicrobial resistance (AMR) and
stagnation in new antibiotic development. Left unchecked, the annual number of deaths attributable to AMR is
estimated to reach 10 million by 2050, exceeding deaths due to cancers and diabetes. Thus, there is an urgent
need to develop innovative approaches to tackle this serious global crisis.
We aim to develop innovative, highly efficient, and biocompatible pH- or ROS-responsive antimicrobial polymer-
drug (i.e., antibiotics) conjugates (PDCs), which can effectively treat serious infectious diseases and overcome
AMR while ensuring high biocompatibility. We will accomplish this goal utilizing existing FDA-approved antibiotics,
disease-specific stimuli, and a uniquely engineered biocompatible cationic polymer. Cationic polymers can be
effective antibiotic carriers as they can induce pores on the bacterial wall/membrane, thus significantly enhancing
the transport of antibiotics into the bacteria and allowing them to bypass the efflux pump in the bacterial
membrane. Cationic PDCs can also (1) stick to the bacteria’s surface, thereby serving as a drug reservoir to
release drug locally, and (2) effectively infiltrate bacterial biofilms, thereby leading to deeper antibiotic penetration.
The strong synergistic effects between cationic polymers and antibiotics diminish the intrinsic resistance of the
pathogens, thus leading to significantly enhanced antimicrobial efficacy, especially for AMR pathogens.
Antibiotics will be conjugated onto the cationic polymer via pH- or ROS-responsive linkers as the inflammatory
microenvironment in infected tissues have low pH levels and high levels of reactive oxygen species (ROS).
Furthermore, we engineered a GSH-cleavable and charge-reversal cationic polymer that can greatly reduce its
systemic toxicity as well as cellular toxicity for mammalian cells. Lastly, PDC capable of stimuli (disease-specific)-
controlled drug release can accumulate preferentially at the infected tissues due to the enhanced permeation
and retention (EPR) effect, thereby further reducing systemic toxicity while achieving high antimicrobial efficacy.
In Aim 1, we will design, synthesize and characterize pH- and ROS-responsive PDCs. We will first investigate
the synergy between a number of free (i.e., before conjugation) FDA-approved antibiotics and our uniquely
designed stimuli-responsive and charge-reversal biocompatible cationic polymer. In Aim 2, the antimicrobial and
antibiofilm efficacies, drug resistance development profiles, and biocompatibilities of the resulting stimuli-
responsive PDCs will be evaluated in multiple bacteria species. In Aim 3, we will systematically determine the
maximum tolerated dose, in vivo biodistribution, antimicrobial efficacy, and potential systemic toxicity of the
selected PDCs in three clinically relevant bacterial infection mouse models.
This study will create a new class of PDCs bas...

## Key facts

- **NIH application ID:** 10300745
- **Project number:** 1R21AI156253-01A1
- **Recipient organization:** UNIVERSITY OF WISCONSIN-MADISON
- **Principal Investigator:** SHAOQIN - GONG
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $191,661
- **Award type:** 1
- **Project period:** 2021-06-01 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10300745

## Citation

> US National Institutes of Health, RePORTER application 10300745, Stimuli-Responsive Polymer-Drug Conjugates: A New Strategy to Fight Antimicrobial Resistance (1R21AI156253-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10300745. Licensed CC0.

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