# Attacking failure of antibiotic treatment by targeting antimicrobial resistance enabler cell-states

> **NIH NIH U19** · BROAD INSTITUTE, INC. · 2022 · $2,362,994

## Abstract

SUMMARY
Deployment of new antimicrobials is promptly circumvented by the rapid evolution of resistance, underscoring
the critical need for new strategies to stay ahead in the arms-race against bacterial pathogens. Developing a
detailed understanding of the circumstances as well as genetic and mechanistic basis for which antibiotic
resistance develops provides opportunities for pre-emptively subverting this process. While infections caused by
organisms harboring antimicrobial resistance (AMR) genes are a major cause of antibiotic treatment failure (ATF),
ATF frequently occurs when the etiological agents are not AMR by traditional susceptibility testing. It is becoming
increasingly recognized that transient cell-states such as tolerance, persistence and hetero-resistance are critical
drivers underlying treatment failure. However, there is a paucity of data with regards to the genetic and
mechanistic basis for these cell-states as well as a lack of diagnostic-detection approaches. ATF cell-states
initially exist as minority variants within a population and display a transient phenotype that tends to dissipate as
the stress subsides, making them challenging to detect and consequently missed in current diagnostic assays.
These enabler cell-states remain mechanistically poorly understood and seem to preferentially arise during
fluctuating treatment regimens, for instance caused by a drug’s PK/PD characteristics, whereby ATF cell-states
can drive the re-emergence of the (susceptible) bacterial infection after antibiotic pressure wanes. Importantly,
this creates opportunities where multi-step high-level resistance mutations are given an extended opportunity to
emerge. Therefore, because antibiotic resistant variants often follow closely on the heels of the occurrence of
ATF cell-states, these cell-states can be viewed as enablers of antibiotic treatment failure and AMR. This
proposal focuses on untangling the importance of ATF cell-states in the emergence of antibiotic
resistance and treatment failure, and designs new approaches and strategies to identify, track and target
them. The main team consists of 4 principal investigators that have a very successful collaboration history.
Together they will work on 5 challenges distributed across 3 projects and supported by an administrative and a
genomics and bioinformatics core. In Challenge: 1) the full profile of possible genetic pathways that can induce
ATF cell-states is determined; 2) treatment regimens that drive the emergence of ATF-cell states are determined;
3) it is determined how ATF cell-states enable the emergence of AMR; 4) drugs and compounds are screened
for, that target ATF cell-state collateral sensitivities; 5) a computational deconvolution approach is developed
that predicts the presence and frequency of ATF cell-states in a complex bacterial population. Overall this
proposal contains a collection of conceptually and technically innovative aspects that are geared towards
understating the gen...

## Key facts

- **NIH application ID:** 10171116
- **Project number:** 1U19AI158076-01
- **Recipient organization:** BROAD INSTITUTE, INC.
- **Principal Investigator:** Vaughn Cooper
- **Activity code:** U19 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $2,362,994
- **Award type:** 1
- **Project period:** 2022-09-12 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10171116

## Citation

> US National Institutes of Health, RePORTER application 10171116, Attacking failure of antibiotic treatment by targeting antimicrobial resistance enabler cell-states (1U19AI158076-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10171116. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*