# Prevalence, Consequences and Mechanisms of Antibiotic Heteroresistance in Cystic Fibrosis

> **NIH NIH R01** · UNIVERSITY OF WASHINGTON · 2022 · $645,617

## Abstract

Project Summary
Progress in improving infection outcomes depends upon understanding factors that diminish antibiotic action.
Recent work suggests antibiotic heteroresistance may be a key factor. Heteroresistant pathogens exhibit
population-level resistance heterogeneity, meaning they contain highly resistant subpopulations, and often
exhibit unstable resistance, meaning some cells become rapidly sensitive when grown without antibiotics.
This proposal focuses on these two phenotypes as they are postulated to have major effects on susceptibility
testing and antibiotic efficacy. Here we propose to study population-level resistance heterogeneity and
unstable resistance in people with cystic fibrosis (CF) and chronic Pseudomonas aeruginosa (Pa)
infections who cycle on and off inhaled tobramycin.
CF offers key advantages for these studies as it is a monogenic disease with uniform manifestations, the
responses of a single bacterial species to the same antibiotic can be studied in sizable cohorts, and
infrastructure exists to procure primary specimens from the infected site (sputum) during antibiotic "on" and
"off" periods. These advantages, and methods developed in our preliminary work enable us to test the
hypotheses that Pa from chronically-infected patients exhibit marked population-level resistance heterogeneity
and unstable resistance; that parameters accounting for these factors predict clinical responses to treatment;
and that unstable resistance in CF Pa is due to a core set of gene amplifications and fitness-compensating
point mutations. This work will generate foundational knowledge about antibiotic heteroresistance that could
improve understanding of antibiotic treatment failure in CF, and suggest new precision medicine approaches to
select antibiotics and improve outcomes. The findings could also guide future work in infections where patient
heterogeneity, pathogen and treatment diversity, and less developed infrastructure make studies more difficult.

## Key facts

- **NIH application ID:** 10339853
- **Project number:** 1R01HL160710-01
- **Recipient organization:** UNIVERSITY OF WASHINGTON
- **Principal Investigator:** PRADEEP k SINGH
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $645,617
- **Award type:** 1
- **Project period:** 2022-09-01 → 2026-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10339853

## Citation

> US National Institutes of Health, RePORTER application 10339853, Prevalence, Consequences and Mechanisms of Antibiotic Heteroresistance in Cystic Fibrosis (1R01HL160710-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10339853. Licensed CC0.

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