# Building re-usable phage and antibiotic treatments via exploitation of bacteria-phage co-evolutionary dynamics

> **NIH NIH R21** · GEORGIA INSTITUTE OF TECHNOLOGY · 2021 · $236,700

## Abstract

Project Summary
Chronic (long-term) bacterial infections are a major medical and public-health challenge, exacerbated by the
rise in antibiotic resistance. As antibiotics often fail to treat these cases, increasing attention is turning to
alternate therapeutics, including bacteriophage (phage) therapy. Like antibiotics, phage therapy faces the
challenge of resistance. Unlike drugs, phages can evolve to overcome bacterial defenses, opening potential for
co-evolutionary dynamics with their targets. Phage evolution has been flagged as a potentially useful attribute
in enhancing total efficacy, but also as a pitfall in ensuring regulatory compliance due to the changing nature of
required treatment. This application proposes that manipulating the co-evolutionary dynamic between bacteria
and phage can promote the re-usability of defined phage treatments against a single evolving bacterial
population.
Co-evolution can occur in two main ways, an escalating ‘arms race dynamic’ (ARD) model, or a diversifying
‘fluctuating selection dynamic’ (FSD) model. Both are observed in phage-bacteria systems, and pilot data
shows that FSD is favored by the addition of stressors including antibiotics. Pilot data further shows that FSD
dynamics promote the effective re-use of a standard phage preparation against a single evolving bacterial
population, as under the FSD regime, bacteria do not evolve broadly generalized resistance. Instead FSD
leads to specialized resistance to the co-evolved phage at the cost of a return to susceptibility to the ancestral
and potentially licensed/approved phage.
The primary hypothesis is that co-evolutionary dynamics can be shifted with the addition of antibiotics –
improving the long-term treatment efficacy by reducing bacterial burden and allowing for repeated application
of a standard licensed phage preparation. The proposal will test this hypothesis in two specific aims:
Aim 1: Assess co-evolutionary dynamics during clinical phage therapy using compassionate release patient
samples. To assess co-evolutionary dynamics in a therapeutic context, the investigators will use clinical
samples from 8 cystic fibrosis patients who received a phage cocktail as part of compassionate release care
Aim 2: Identify phage and antibiotic factors that shift co-evolutionary dynamics in clinical PA isolates. Aim 1
provides a window into clinical co-evolutionary dynamics but does not allow a direct test of the impact of
different treatment designs. To assess the factors that promote FSD co-evolutionary dynamics and treatment
re-usability, the investigators will conduct in vitro mock phage therapy to recapitulate and expand on the
compassionate release work in a synthetic sputum medium.

## Key facts

- **NIH application ID:** 10130092
- **Project number:** 1R21AI156817-01
- **Recipient organization:** GEORGIA INSTITUTE OF TECHNOLOGY
- **Principal Investigator:** Samuel Paul Brown
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $236,700
- **Award type:** 1
- **Project period:** 2020-12-09 → 2022-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10130092

## Citation

> US National Institutes of Health, RePORTER application 10130092, Building re-usable phage and antibiotic treatments via exploitation of bacteria-phage co-evolutionary dynamics (1R21AI156817-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10130092. Licensed CC0.

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