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A comprehensive investigation of Pseudomonas quorum sensing regulatory relationships and the consequences on quorum sensing inhibitors in complex communities

Award Number: R01AI177555
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Our overarching goal is to develop efficacious strategies to combat multidrug-resistant (MDR) pathogens, a growing healthcare threat. Quorum sensing (QS) inhibition is an attractive anti-microbial approach, as it represents an anti-virulence strategy fundamentally different from current traditional therapies. QS a highly conserved bacterial communication signaling regulatory mechanism controlling numerous virulence functions and inter- and intraspecies interactions in mono- and polymicrobial communities. The recalcitrant ESKAPE pathogen Pseudomonas aeruginosa (PA) exemplifies a highly problematic nosocomial pathogen with astounding complex interconnected QS systems controlling multiple virulence functions and regulating antagonism or synergism with other microbes. QS relevance in pathogenesis has been recognized; however, the regulatory interrelationships of these systems during infection and in polymicrobial settings have been studied primarily in vitro, limiting relevance to the human environment during infection and leaving answered fundamental questions that will aid in combatting MDR infections by utilizing the anti-virulence/anti-QS approach. We hypothesize that the interrelationships between the three QS systems are significant drivers of infection severity, interspecies interactions, and microbial community composition. In turn, we anticipate that our anti-QS lead compound will restrict infection exacerbations and promote microbial homeostasis. We propose to assess this hypothesis paradigmatically by leveraging an extensive collection of PA QS mutants and a novel anti-QS compound in dynamic and human-relevant host environments to identify specific infection-relevant host-microbe and microbe-microbe interactions and dissect the mechanisms underlying these interactions. Specifically, in the proposed three Aims, we will address three fundamental questions that will fill existing gaps: 1) What are the regulatory relationships and functions of the three major PA QS systems? 2) How do anti-QS therapies impact infection severity and QS regulatory interactions in PA mono- and polymicrobial settings? and 3) How do the QS systems and inhibitors impact the development of resistance and limit perturbations of host-associated microbial communities? Answering these questions will not only provide critical insights into long-standing questions about the anti-virulence approach and the role of QS mutations in PA virulence but will also uncover how the in vivo environment impacts the regulatory interrelationships of the three QS systems and QS-dependent inter- and intraspecies interactions. By tapping into bacterial QS pathways with novel potent and highly specific anti-QS compounds, we aim to treat infections while preserving the composition and protective function of the microbiota. Results from these dynamic settings may aid in the fight against antibiotic resistance and provide fundamental insights into the molecular mechanisms underlying the virulence of complex infections and microbial interactions in vivo.


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: 2024 ( Subtotal = $750,050 )
2024	2024	THE GENERAL HOSPITAL CORPORATION	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	2	6/28/2024	NON-COMPETING CONTINUATION	$750,050
														Subtotal = $750,050

Issue Date FY: 2023 ( Subtotal = $753,257 )
2023	2023	THE GENERAL HOSPITAL CORPORATION	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	1	6/29/2023	NEW	$753,257
														Subtotal = $753,257

Grand Total All Awards = $1,503,307

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A comprehensive investigation of Pseudomonas quorum sensing regulatory relationships and the consequences on quorum sensing inhibitors in complex communities

Award Number: R01AI177555

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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