# Collateral Consequences of Enabler Genotypes in Antibiotic Treatment Failure.

> **NIH NIH U19** · BROAD INSTITUTE, INC. · 2022 · $438,766

## Abstract

Project 2: Collateral Consequences of Enabler Genotypes in Antibiotic Treatment Failure
Antibiotic treatment failure (ATF) is of critical medical importance as delays in effective antibiotic therapy
promotes prolonged morbidity and increase mortality leading to overall poorer patient outcomes. While
antibiotic resistance is one primary mechanism for ATF, the roles for transient cell-states conferring
antibiotic tolerance, persistence, and hetero-resistance, herein referred to as “enablers” are increasingly
recognized as a major mechanism for bacterial evasion of antibiotic therapy. These enabler bacterial
populations are of considerable scientific and medical importance as typically precede the subsequent
evolution or acquisition of high-level resistance mechanisms, making these populations a “canary in the coal
mine” for understanding how resistance and treatment failures can emerge. Enabler mutants identified thus
far in central cellular pathways indicate commonalities for developing an enabler state suggest these
findings will be broadly applicable in a cross-species manner. Our underlying hypothesis is that the
collateral phenotypes of enabler genotypes can be identified and rationally targeted to optimize the
treatment outcomes and prevent subsequent acquisition of high-level resistance. We plan on using a
multifaceted approach to understand the genetic and mechanistic basis of enabler mutations. We will
experimentally select for enabler mutations using continuously variable antibiotic exposures in both
sensitive strains and those with defined enabler mutations. These antibiotic sensitive but tolerant
populations will be used to model the impact of different enabler genotypes on the probability and genetic
pathways to subsequent evolution of high-level antibiotic resistance, the role of these genotypes on
horizontal transfer of resistance, and how enabler mutants impact antibiotic treatment failure in vivo. These
enabler strains will be used to model how the respective genotypes, upon antibiotic exposure, affect key
pathways such as bacterial stringent response, transcriptional signaling, and translational fidelity, and how
this in turn leads to the production of enabler phenotypes. These lines of investigation will provide insight
into whether different enabler genotypes have common mechanistic underpinnings. We also plan to
examine if rational targeting of enablers could provide therapeutic benefit to either stop the spread of
resistance or improve antibiotic efficacy when enabler mutants are present. Enabler mutations are often
associated with collateral consequences that confer sensitivity or resistance to metabolic of chemical
stresses. We will determine the possibility of exploiting these cross-sensitivities by both targeted and
unbiased chemical screening approaches. These synergies will then be investigated for their capacity to
prevent emergence of enabler mutants as well as their capacity to more effectively treat infections caused...

## Key facts

- **NIH application ID:** 10171120
- **Project number:** 1U19AI158076-01
- **Recipient organization:** BROAD INSTITUTE, INC.
- **Principal Investigator:** Jason W. Rosch
- **Activity code:** U19 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $438,766
- **Award type:** 1
- **Project period:** 2022-09-12 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10171120

## Citation

> US National Institutes of Health, RePORTER application 10171120, Collateral Consequences of Enabler Genotypes in Antibiotic Treatment Failure. (1U19AI158076-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10171120. Licensed CC0.

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