# Global Circuitry that Controls Acinetobacter Resistance and Virulence

> **NIH NIH R01** · NORTHEASTERN UNIVERSITY · 2024 · $392,500

## Abstract

PROJECT SUMMARY
 Acinetobacter baumannii is among the most antibiotic-resistant pathogens known, and the
emergence of isolates with enhanced virulence poses an urgent public health challenge. Understanding
how the microorganism thwarts antibiotic and immune attack via its protective cell envelope is essential to
developing new strategies for controlling this threat. Envelope synthesis and integrity in bacteria are
typically maintained by a large number of response systems that control specific aspects of the envelope. A.
baumannii, however, has diverged substantially from this paradigm. The pathogen lacks orthologs of many
canonical envelope response proteins and instead relies on a single two-protein regulatory system to
globally modulate every layer of the envelope and control both antibiotic resistance and ability to
cause disease. This unique system, known as BfmRS, lowers susceptibility to a wide range of drugs,
antagonizes innate immune killing, and facilitates development of lethal disease in mice. Intriguingly, a
clinical isolate showing enhanced virulence requires the system for growth. BfmRS is therefore tightly linked
to the intractability of infections with the pathogen and represents a key potential therapeutic target. Despite
its fundamental importance, we lack an understanding of how the large BfmRS regulon controls broad-
range drug resistance and pathogenicity, and what signals the system senses. The objective of the
proposed studies is to understand how A. baumannii uses a single control circuit to simultaneously
modulate resistance and virulence. Our central hypothesis is that BfmRS jointly controls the barrier to both
drug penetration and innate immune attack by modulating the level of key outer membrane (OM) structures
in response to disruptions in envelope protein production. We will test this hypothesis by pursuing three
Aims, which build on our extensive preliminary data defining the BfmRS regulon and its chemical-genetic
profile, as well as the phosphorylation cascade it uses for signaling. In Aim 1 we will test the model that
BfmRS controls the bacterial interface with both antibiotics and innate immune effectors by modulating the
OM barrier. In Aim 2, we will identify the antibiotic-induced and intrinsic stress signals that are sensed by
BfmRS. In Aim 3, we will define the relationship between variability in BfmRS activity, growth-dependence,
and virulence across diverse patient isolates as a test of the model that variation in BfmRS signaling level is
a driver of enhanced virulence in invasive strains. This work will elucidate the mechanisms by which a
unique regulatory system controls both resistance and pathogenicity in a critically important nosocomial
microbe. These results will inform strategies for potentiating antibiotic and immune action for killing
extensively drug-resistant bacteria.

## Key facts

- **NIH application ID:** 10877925
- **Project number:** 5R01AI162996-04
- **Recipient organization:** NORTHEASTERN UNIVERSITY
- **Principal Investigator:** Edward Geisinger
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $392,500
- **Award type:** 5
- **Project period:** 2021-07-26 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10877925

## Citation

> US National Institutes of Health, RePORTER application 10877925, Global Circuitry that Controls Acinetobacter Resistance and Virulence (5R01AI162996-04). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10877925. Licensed CC0.

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