# Fitness of gram-negative pathogens during bacteremia

> **NIH NIH R01** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2020 · $693,079

## Abstract

We are losing the battle against antibiotic-resistant Gram-negative bacterial pathogens in our hospitals and
clinical care facilities. The CDC estimates that over 2 million people are infected annually with 17 species of
antibiotic-resistant bacterial pathogens, killing 23,000 people per year. Over half of the species are Gram-
negative pathogens including carbapenem-resistant Enterobacteriaceae (CRE) and the non-fermenting
opportunistic pathogen Acinetobacter baumannii. Although the CDC described carbapenem-resistant (CR)
bacteria as “nightmare bacteria”, the factors required for virulence of these pathogens or their antibiotic-
susceptible counterparts during bloodstream infections are largely unknown. Thus, there is an urgent need to
identify unique (species-specific) and common (required by most of the six Gram-negative species) fitness and
virulence factors required by these species for bacteremia, and map key metabolic pathways and essential gene
sets used by these pathogens in vivo. Our long-term goal is to delineate the mechanisms of pathogenesis in
Gram-negative bacteria that cause hospital-acquired infections. The overall objective of this application is to
conduct RNA-seq and measure in vivo growth rates in representative isolates of E. coli, Klebsiella pneumoniae,
Serratia marcescens, Citrobacter freundii, and Enterobacter cloacae as well as A. baumannii, in the murine
model of bacteremia in which Tn-seq has been largely completed for these isolates. Our central hypothesis is
that based on the relatedness of CR species at the family (Enterobacteriaceae) and class (A. baumannii) levels,
these pathogens require a combination of orthologous core functions and species-specific fitness factors to
acquire nutrients and evade host responses during bacteremia. The rationale for these proposed studies is that
antibiotic resistance is rising rapidly in Gram-negative pathogens that cause bloodstream infections in our health
care systems. We plan to objectively identify unique and common genes critical for bloodstream infection by
antibiotic-susceptible and CR bacteria and measure their in vivo gene expression. Unique and common virulence
determinants will be investigated to determine mechanisms of pathogenesis. We will test our central hypothesis
and attain the objective of this application by completing these specific aims: 1) Define the active metabolic
pathways and resultant growth kinetics across six Gram-negative pathogens during bacteremia. 2) Identify
shared and unique pathways required for bacteremia by six Gram-negative pathogens. Specific expected
outcomes will include: (a) precise measurement of growth kinetics of each pathogen during bacteremia, (b)
identification of preferred and required pathways at equivalent growth phases in vivo, and (c) detailed maps of
these pathways annotated with genes that are pathogen-specific or shared across multiple pathogens. The
positive impact of these studies will be substantial. We will uncover mec...

## Key facts

- **NIH application ID:** 9989049
- **Project number:** 5R01AI134731-02
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Michael Abbott Bachman
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $693,079
- **Award type:** 5
- **Project period:** 2019-08-05 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9989049

## Citation

> US National Institutes of Health, RePORTER application 9989049, Fitness of gram-negative pathogens during bacteremia (5R01AI134731-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9989049. Licensed CC0.

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