# Development of Nanoparticle Antibiotic Adjuvant for the Treatment of Chronic Suppurative Otitis Media

> **NIH NIH R21** · STANFORD UNIVERSITY · 2020 · $237,575

## Abstract

Project Summary / Abstract
We request NIH support to investigate the use of functionalized gold nanoclusters as an adjuvant therapy for
chronic suppurative otitis media (CSOM). CSOM is characterized by a chronically discharging infected middle
ear that is most frequently caused by Pseudomonas aeruginosa (PA) and is a leading cause of permanent
hearing loss. In CSOM, PA exists in bacterial communities known as biofilms. Fluoroquinolone eardrops are
the primary method of treatment due to its non-ototoxicity. However, this treatment is ineffective in fully
eradicating the infection. This is a result of the inability of fluoroquinolone to target a subpopulation of
metabolically inactive bacteria known as persister cells within the biofilms. Persister cells repopulate the
biofilm niche after therapy is discontinued, causing a relapse of CSOM. The end result is multiple rounds of
surgery and a lifelong struggle with this disease. There is a large unmet medical need to develop new
medical therapies aimed at persister cells in biofilms of CSOM.
Our lab has recently created and validated a novel PA CSOM animal model with bioluminescent strains of
PA allowing real time tracking of disease. It mimics the human condition by persisting beyond six months, is
recalcitrant to topical fluoroquinolone therapy, and leads to hair cell death (i.e. hearing loss) over time. Using
our unique model of PA CSOM, we are now able to test novel therapeutics for CSOM. Consequently, we
have created an anionic hydrophilically functionalized gold nanocluster covalently conjugated with
cell penetrating peptide (AuNC@CPP) as an adjuvant for fluoroquinolones. We have shown, in vitro,
that co-administration of the AuNC@CPP with ofloxacin completely eliminates persister cells in both
stationary phase and biofilms of PA. The exceptional killing ability of AuNC@CPP plus ofloxacin opens up the
possibility to develop the first therapeutic that specifically targets PA CSOM.
We theorize that our AuNC@CPP combined with ofloxacin therapy can eradicate PA CSOM in vivo. Because
our preliminary data shows that AuNC@CPP does not increase intracellular ofloxacin concentration, we
hypothesize that AuNC@CPP acts as both an enhancer of reactive oxygen species (ROS)-mediated
ofloxacin lethality and inhibits bacterial DNA repair. We propose to determine the mechanism(s) behind how
AuNC@CPP potentiates ofloxacin lethality of persister cells by measuring intracellular ROS production and
evaluating RecA inhibition followed by in vivo studies for efficacy and ototoxicity in comparison to ofloxacin
alone. The proposed work will develop the first adjuvant therapy that specifically targets recalcitrant CSOM
and lays the foundation for future research of this treatment in other chronic biofilm infections.

## Key facts

- **NIH application ID:** 10043101
- **Project number:** 1R21AI154097-01
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** Peter Luke Santa Maria
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $237,575
- **Award type:** 1
- **Project period:** 2020-07-01 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10043101

## Citation

> US National Institutes of Health, RePORTER application 10043101, Development of Nanoparticle Antibiotic Adjuvant for the Treatment of Chronic Suppurative Otitis Media (1R21AI154097-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10043101. Licensed CC0.

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