# Antibiotic Potentiators Targeting Biofilms of MRSA and MRSE

> **NIH NIH R03** · UNIVERSITY OF OKLAHOMA · 2020 · $70,563

## Abstract

Project Summary/Abstract:
 Penicillin binding protein 2a (PBP2a) is the leading cause of β-lactam antibiotic resistance in deadly
Staphylococcus aureus and Staphylococcus epidermidis infections. Morbidity, mortality, and health care costs
create a critical need for antibiotics that can overcome PBP2a. New antibiotic development has led to success
against planktonic bacteria but methicillin-resistant S. aureus (MRSA) and methicillin-resistant S. epidermidis
(MRSE) biofilms continue to cause deadly hospital-acquired infections (HAIs). These factors are barriers to the
“prompt and serious action” urged by the Centers for Disease Control. As discovered in our laboratory, β-lactam
antibiotics that kill methicillin-susceptible S. aureus also prevent the growth of methicillin-resistant S. aureus
(MRSA) if administered with branched poly(ethylenimine), BPEI. The β-lactam + BPEI combinations are also
effective against exopolymers surround MRSE bacteria. This route to reduce morbidity, mortality, and health
care costs will remain closed without experiments to maximize potency.
 Our long-term goal is to kill bacterial pathogens and their associated biofilms. The overall objective is to
determine if antibiotics that target bacterial pathogens (β-lactams, vancomycin, linezolid, rifampicin) are
potentiated against MRSA and MRSE that express biofilm extracellular polymeric substances (EPS) and the
mecA gene responsible for PBP2a expression. The central hypothesis is that resistance from EPS and PBP2a
can be conquered when wall teichoic acid (WTA) is disabled by cationic polymer potentiators. This effect may
arise from electrostatic interactions between BPEI and WTA. The rationale underlying the proposed research is
that BPEI disrupts the biofilm architecture and counteracts resistance from mecA, making MRSA and MRSE
susceptible to β-lactam antibiotics. In our opinion, the rationale departs from the status quo of stopping WTA
biosynthesis. Low protein binding and potency in serum are retained. Drug safety is increased by linking
potentiators to non-toxic poly(ethylene glycol), PEG, molecules. An in vivo study shows the maximum tolerable
dose is over 200 mg/kg.
 The study design to test the central hypothesis involves pursuit of the following specific aims. Aim 1,
Create a library of anti-biofilm potentiators. Aim 2, Identify which potentiators have greatest anti-biofilm activity
when used in combination with antibiotics. Data from these aims will demonstrate the possibility of improving the
health outcomes of persons afflicted with staphylococcal infections. In our opinion, this route is innovative by the
use of PEGylated potentiators to deactivate anionic teichoic acid through electrostatic interactions. The impact
on the research community is a pathway that enables vertical advancement of antibiotic drug discovery by
providing ways for other researchers to reinvigorate efforts that have failed to overcome resistance in biofilms.

## Key facts

- **NIH application ID:** 9823864
- **Project number:** 5R03AI142420-02
- **Recipient organization:** UNIVERSITY OF OKLAHOMA
- **Principal Investigator:** Charles V Rice
- **Activity code:** R03 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $70,563
- **Award type:** 5
- **Project period:** 2018-11-15 → 2021-10-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9823864

## Citation

> US National Institutes of Health, RePORTER application 9823864, Antibiotic Potentiators Targeting Biofilms of MRSA and MRSE (5R03AI142420-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9823864. Licensed CC0.

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