# Bacterial genomics: multiscale investigation of host adaptation, unexplained resistance and plasmid dynamics

> **NIH NIH U19** · BROAD INSTITUTE, INC. · 2024 · $2,198,637

## Abstract

Bacterial pathogens continue to pose an urgent threat to public health, adapting rapidly to a changing
landscape of antibiotic use, and claiming millions of lives worldwide each year. The ongoing emergence and
widespread dissemination of new bacterial threats, with increased virulence, antibiotic resistance, and
transmissibility, demand urgent attention on a global scale. There are critical gaps in our understanding of the
adaptive strategies these pathogens deploy to i) evade the host immune system, ii) respond to therapeutic
interventions, and iii) rapidly disseminate locally and globally; thereby, limiting our ability to successfully prevent
and treat bacterial infections. Our long-term goal is to build upon our established track record of technological
and bioinformatic innovation through the development, optimization and application of cutting-edge sequencing
technologies, high-throughput molecular and multi-omic approaches and computational tools to shed new light
on bacterial dynamics and their adaptive strategies. Together with our long-standing collaborations with a
range of multidisciplinary world-renowned experts, and access to large, unique, systematic collections of
pathogens, genomes and clinical data, we are optimally positioned to fill outstanding knowledge gaps for
pressing infectious diseases.
 In this proposal, we will explore the adaptation and spread of high priority bacterial threats across the
following three specific aims: i) We will characterize Neisseria gonorrhoeae’s genetic and transcriptional
adaptation to anatomical sites of infection and host immune pressures. This will be achieved using long-read
sequencing technology paired with an innovative pangenome hybrid selection technique to enrich gonorrhoeal
DNA and RNA directly from patient specimens, providing insights into within-host genomic and transcriptomic
diversity. ii) We will identify cryptic resistance factors in carbapenem-resistant Enterobacterales and
Pseudomonas aeruginosa, where resistance remains unexplained in >20% of cases. For a collection of
clinically collected isolates lacking characterized carbapenem resistance mechanisms, we will perform bulk
RNA-Seq and a novel single-cell bacterial RNA-Seq approach to elucidate differential expression and
transcriptional heterogeneity driving resistance, and functionally test our predictions. iii) We will explore the
epidemiological and evolutionary dynamics of plasmids, and their role in disseminating virulence and drug
resistance genes. We will accomplish this by applying novel computational algorithms designed to limit the
need for expensive long-read data to isolate collections spanning different populations and timescales. The
expected outcome of this project is a more complete understanding of the within-host dynamics, adaptation
and spread of bacterial pathogens, which will provide critical evidence for the future development of
prophylaxis, treatment and infection control measures. In addition, this pro...

## Key facts

- **NIH application ID:** 10853972
- **Project number:** 2U19AI110818-11
- **Recipient organization:** BROAD INSTITUTE, INC.
- **Principal Investigator:** Ashlee Miriam Earl
- **Activity code:** U19 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $2,198,637
- **Award type:** 2
- **Project period:** 2014-04-10 → 2027-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10853972

## Citation

> US National Institutes of Health, RePORTER application 10853972, Bacterial genomics: multiscale investigation of host adaptation, unexplained resistance and plasmid dynamics (2U19AI110818-11). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10853972. Licensed CC0.

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