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Design and Synthesis of Small-Molecule Inhibitors of Enteropathogenic Bacterial Virulence

Award Number: F31AI124549
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 09/01/2017
PERIOD OF PERFORMANCE END DATE: 08/31/2018

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Design and Synthesis of Small-Molecule Inhibitors of Enteropathogenic Bacterial Virulence - Abstract Enteric diarrheal disease continues to be a global health concern. Acute diarrhea is a leading cause of death in young children worldwide and is one of the most commonly reported illnesses in the United States. Enteric disease spreads quickly in areas lacking adequate sanitation and drinking water, as ingestion of the waterborne bacteria commonly results in vomiting and diarrhea, and subsequently, further contamination. The transcriptional cascade initiated by bacterial infection ultimately leads to the expression of virulence factors, including toxins, effector molecules, and colonization factors. It is by understanding the mechanism of bacterial virulence that we may understand the role of virulence factors in pathogenesis and identify effective therapeutics. Virulence-specific treatment methods would be especially significant given the rise in antimicrobial (drug) resistance. In particular, this study aims to exploit the fatty acid regulatory mechanism used by ToxT, a primary transcription factor involved in Vibrio cholerae virulence, to design a subset of compounds that may act as anti-virulence agents. The goals of the proposed research are to design and synthesize small-molecule inhibitors (Aim 1) and characterize their effects on the activity of ToxT (Aim 2) and other members of the AraC/XylS superfamily of proteins (Aim 3). Preliminary data supports our hypothesis that designing compounds that mimic the structure of the natural fatty acid ligand in ToxT in its protein-bound conformation will lead to potent ToxT inhibition. These studies will result in the synthesis and characterization of novel small molecules that specifically target V. cholerae virulence factors. Given the similarity of ToxT to virulence gene regulators in other bacteria, the proposed studies could also lead to effective drug candidates for numerous other enteric bacterial infections, including cholera, travelers' diarrhea, and dysentery.


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: 2021 ( Subtotal = -$672 )
2021	2017	TRUSTEES OF DARTMOUTH COLLEGE	6001 PARKHURST HALL STE 207	HANOVER	NH	03755	GRAFTON	USA	Allergy and Infectious Diseases Research	000	1	12/30/2020	NEW	-$672
														Subtotal = -$672

Issue Date FY: 2018 ( Subtotal = $0 )
2018	2017	TRUSTEES OF DARTMOUTH COLLEGE	1 HINMAN DARTMOUTH COLLEGE	HANOVER	NH	03755	GRAFTON	USA	Allergy and Infectious Diseases Research	000	1	8/9/2018	NEW	$0
														Subtotal = $0

Issue Date FY: 2017 ( Subtotal = $44,044 )
2017	2017	TRUSTEES OF DARTMOUTH COLLEGE	1 HINMAN DARTMOUTH COLLEGE	HANOVER	NH	03755	GRAFTON	USA	Allergy and Infectious Diseases Research	001	1	8/15/2017	NEW	$0
2017	2017	TRUSTEES OF DARTMOUTH COLLEGE	1 HINMAN DARTMOUTH COLLEGE	HANOVER	NH	03755	GRAFTON	USA	Allergy and Infectious Diseases Research	000	1	8/15/2017	NEW	$44,044
														Subtotal = $44,044

Grand Total All Awards = $43,372

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Design and Synthesis of Small-Molecule Inhibitors of Enteropathogenic Bacterial Virulence

Award Number: F31AI124549

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 09/01/2017

PERIOD OF PERFORMANCE END DATE: 08/31/2018

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