Structure-based microbially targeted prodrugs

Ended Project Grant Awarded Last action

Award ID
R01AI171514
Recipient
Awarding agency
Obligated
$6,433,924

Award facts

Assistance listing
93.855 Allergy and Infectious Diseases Research
Completion date
Place of performance
Pennsylvania, USA

Award details come from USAspending.gov.

Description

As the agency reported it.

Abstract
Antimicrobial drug resistance is an ongoing challenge for many serious diseases, including staphylococcal infections. Development of new antibiotics to combat methicillin-resistant staphylococcus aureus-labeled a "serious threat" by the CDC-is a high priority. During drug development efforts, poor cellular penetration and drug-like features of compounds are a common roadblock. The studies in this proposal will advance a novel strategy to overcome this roadblock, by employing a prodrug approach, in which a bipartite molecule is activated intracellularly to release the active "warhead." central to our strategy is the determination of structure-activity relationships that define selective prodrug activation within s. Aureus bacteria. We will advance this strategy by evaluating our preliminary prodrug SAR using two classes of inhibitors that are distinct in chemical structure and intracellular target. We will determine the enzymatic selectivity and evaluate how prodrugging alters biological properties of inhibitors, using in vitro and in vivo assays. In addition, we will use crystallographic approaches to delineate the structural features that define selective substrate recognition. Together, this project will establish and validate our approach for subsequent pre-clinical optimization of much-needed new antistaphylococcal therapies.

Transactions

Action Obligated Date
Amendment $0
Amendment $1,535,250
Amendment $1,535,250
Amendment $0
Amendment $0
Amendment $798,784
Amendment $816,384
Amendment $874,128
Original award $874,128

Subawards

Subrecipient Amount Awarded
The Washington University Structure-based microbially targeted prodrugs (Dowd - Jez) $166,081
George Washington University (The) Thisproject involvesthesynthesisandtestingofsmallmoleculesandtheirprodrugs againstvariousStaphylococcusspecies.TheDowdLaboratoryatGeorgeWashington… $123,579
The Washington University The laboratory of Dr. Joseph Jez will perform x-ray crystallographic analysis of GloB and FrmB, as well as other proteins, in support of biochemical and drug… $162,567
George Washington University (The) This project involves the synthesis and testing of small molecules and their prodrugs against various Staphylococcus species. The Dowd Laboratory at George… $119,182
The Washington University The laboratory of Dr. Joseph Jez will perform x-ray crystallographic analysis of GloB and FrmB, as well as other proteins, in support of biochemical and drug… $164,119
George Washington University (The) This project involves the synthesis and testing of small molecules and their prodrugs against various Staphylococcus species. The Dowd Laboratory at George… $490,660
The Washington University The laboratory of Dr. Joseph Jez will perform x-ray crystallographic analysis of GloB and FrmB, as well as other proteins, in support of biochemical and drug… $828,203

Quick answers

Who received award R01AI171514?

R01AI171514 was awarded to The Children's Hospital Of Philadelphia by National Institute of Allergy and Infectious Diseases (National Institutes of Health) on September 1, 2022.

How much is award R01AI171514 worth?

$6,433,924 has been obligated on R01AI171514.

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