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Repurposing novel selective drugs for treatment and decolonization of vancomycin resistant enterococci

Award Number: R01AI148523
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Repurposing novel selective drugs for treatment and decolonization of vancomycin resistant enterococci - Project Abstract: Vancomycin-resistant enterococci (VRE) is the second leading cause of drug-resistant hospital-acquired infections (HAIs) in the US, triggering the Centers for Disease Control and Prevention to classify VRE as a serious healthcare threat. Despite the prevalence and severity of VRE infections, there are limited number of effective therapeutic options available for treatment. Moreover, the drugs that are available are also detrimental to the normal gut microbiota ultimately contributing the problematic cycle of microbial imbalance known as dysbiosis, which enterococcus takes advantage of in the first place. Thus, there is a significant need for a treatment that can be used to clear both symptomatic and asymptomatic enterococcus colonization without damaging the homeostasis of normal gut flora. Unlike the costly and time-consuming process of de novo drug discovery, drug repurposing is a novel method to reduce the time, cost and risk associated with drug innovation. Studies proposed in this application build upon discoveries of the potent and narrow spectrum antimicrobial activity of the FDA-approved drugs, carbonic anhydrase inhibitors (CAIs) (acetazolamide, dorzolamide, brinzolamide, ethoxzolamide, methazolamide, and dichlorphenamide), in an applicable clinical range, against highly multidrug-resistant enterococci, including VRE. We have demonstrated both in vitro and in vivo that CAIs are superior to drug of choice, linezolid, and can be used for treatment of serious VRE infections as well as VRE decolonization without harming gut microbiota. In addition, we were able to identify a novel antimicrobial target specific for enterococci that could be exploited in future screening campaigns for new inhibitory scaffolds. Our team has embarked upon medicinal chemistry optimization and improved the potency of the scaffold versus VRE by 570-fold (MIC = 0.007 µg/ml for most potent analog) while maintaining no antibacterial activity against normal gut microbiota. We propose to continue lead optimization and assess the in vivo efficacy in various VRE mouse models as well evaluate the novel inhibitor’s safety and PK profiles to support future lead selection and investigational new drug enabling studies.


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: 2023 ( Subtotal = $608,362 )
2023	2023	VIRGINIA POLYTECHNIC INSTITUTE & STATE UNIVERSITY	300 TURNER ST NW	BLACKSBURG	VA	24060	MONTGOMERY	USA	Allergy and Infectious Diseases Research	000	6	7/28/2023	NON-COMPETING CONTINUATION	$608,362
														Subtotal = $608,362

Issue Date FY: 2022 ( Subtotal = $618,044 )
2022	2022	VIRGINIA POLYTECHNIC INSTITUTE & STATE UNIVERSITY	300 TURNER ST NW	BLACKSBURG	VA	24060	MONTGOMERY	USA	Allergy and Infectious Diseases Research	001	5	8/25/2022	NON-COMPETING CONTINUATION	$619,644
2022	2019	PURDUE UNIVERSITY	2550 NORTHWESTERN AVE STE 1900	WEST LAFAYETTE	IN	47906	TIPPECANOE	USA	Allergy and Infectious Diseases Research	000	1	6/29/2022	NEW	-$1,600
														Subtotal = $618,044

Issue Date FY: 2021 ( Subtotal = $645,971 )
2021	2021	VIRGINIA POLYTECHNIC INSTITUTE AND STATE UNIVERSITY	300 TURNER ST NW STE 4200	BLACKSBURG	VA	24061	MONTGOMERY	USA	Allergy and Infectious Diseases Research	002	4	8/10/2021	NON-COMPETING CONTINUATION	$645,971
2021	2020	VIRGINIA POLYTECHNIC INSTITUTE AND STATE UNIVERSITY	300 TURNER ST NW STE 4200	BLACKSBURG	VA	24061	MONTGOMERY	USA	Allergy and Infectious Diseases Research	005	3	9/14/2021	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$575,065
2021	2020	VIRGINIA POLYTECHNIC INSTITUTE AND STATE UNIVERSITY	300 TURNER ST NW STE 4200	BLACKSBURG	VA	24061	MONTGOMERY	USA	Allergy and Infectious Diseases Research	001	3	4/2/2021	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$620,749
2021	2020	PURDUE UNIVERSITY	155 S GRANT ST	WEST LAFAYETTE	IN	47907	TIPPECANOE	USA	Allergy and Infectious Diseases Research	000	2	4/2/2021	NON-COMPETING CONTINUATION	-$620,749
2021	2020	PURDUE UNIVERSITY	2550 NORTHWESTERN AVE STE 1900	WEST LAFAYETTE	IN	47906	TIPPECANOE	USA	Allergy and Infectious Diseases Research	004	2	9/14/2021	NON-COMPETING CONTINUATION	-$130,566
2021	2019	PURDUE UNIVERSITY	2550 NORTHWESTERN AVE STE 1900	WEST LAFAYETTE	IN	47906	TIPPECANOE	USA	Allergy and Infectious Diseases Research	003	1	9/14/2021	NEW	-$444,499
														Subtotal = $645,971

Issue Date FY: 2020 ( Subtotal = $751,315 )
2020	2020	PURDUE UNIVERSITY	155 S GRANT ST	WEST LAFAYETTE	IN	47907	TIPPECANOE	USA	Allergy and Infectious Diseases Research	000	2	7/28/2020	NON-COMPETING CONTINUATION	$751,315
														Subtotal = $751,315

Issue Date FY: 2019 ( Subtotal = $751,315 )
2019	2019	PURDUE UNIVERSITY	155 S GRANT ST	WEST LAFAYETTE	IN	47907	TIPPECANOE	USA	Allergy and Infectious Diseases Research	000	1	9/19/2019	NEW	$751,315
														Subtotal = $751,315

Grand Total All Awards = $3,375,007

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Repurposing novel selective drugs for treatment and decolonization of vancomycin resistant enterococci

Award Number: R01AI148523

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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