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Global Circuitry that Controls Acinetobacter Resistance and Virulence

Award Number: R01AI162996
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/26/2021
PERIOD OF PERFORMANCE END DATE: 06/30/2026

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Global Circuitry that Controls Acinetobacter Resistance and Virulence - 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.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $392,500 )
2025	2025	NORTHEASTERN UNIVERSITY	360 HUNTINGTON AVE	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	5	7/2/2025	NON-COMPETING CONTINUATION	$392,500
														Subtotal = $392,500

Issue Date FY: 2024 ( Subtotal = $392,500 )
2024	2024	NORTHEASTERN UNIVERSITY	360 HUNTINGTON AVE	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	4	6/24/2024	NON-COMPETING CONTINUATION	$392,500
														Subtotal = $392,500

Issue Date FY: 2023 ( Subtotal = $391,810 )
2023	2023	NORTHEASTERN UNIVERSITY	360 HUNTINGTON AVE	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	3	6/29/2023	NON-COMPETING CONTINUATION	$391,810
														Subtotal = $391,810

Issue Date FY: 2022 ( Subtotal = $391,810 )
2022	2022	NORTHEASTERN UNIVERSITY	360 HUNTINGTON AVE	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	2	6/22/2022	NON-COMPETING CONTINUATION	$391,810
														Subtotal = $391,810

Issue Date FY: 2021 ( Subtotal = $379,960 )
2021	2021	NORTHEASTERN UNIVERSITY	360 HUNTINGTON AVE	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	1	7/23/2021	NEW	$379,960
														Subtotal = $379,960

Grand Total All Awards = $1,948,580

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Global Circuitry that Controls Acinetobacter Resistance and Virulence

Award Number: R01AI162996

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 07/26/2021

PERIOD OF PERFORMANCE END DATE: 06/30/2026

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