Studies of lipoamide dehydrogenase tight binding inhibition in tuberculous and non-tuberculous mycobacteria
Active Project Grant Awarded Last action
- Award ID
- R01AI175342
- Recipient
-
Weill Medical College Of Cornell University UEI YNT8TCJH8FQ8
- Awarding agency
-
National Institute of Allergy and Infectious Diseases
National Institutes of Health, Department of Health and Human Services
- Obligated
- $3,522,493
Award facts
- Assistance listing
- 93.855 Allergy and Infectious Diseases Research
- Completion date 59% complete
- Place of performance
- New York, NY 10065, USA
Award details come from USAspending.gov.
Description
- Abstract
- Tuberculosis (TB) is the leading cause of death from a single infection worldwide, with an annual death toll of over 1.6 million lives. TB is curable and drug regimens can be above 90% effective if completed but are long and toxic leading to noncompliance and emergence of resistance. New treatment options relying on novel and unexplored targets are scarce. The bpal regimen recently approved by the FDA features, for the first time in many decades, drugs against new MTB targets (ATP synthase) and with novel mode of action (nitroimidazoles). Nevertheless, more inhibitors against previously unexplored targets are urgently needed to sustain the TB drug pipeline, as resistance is already detected to components of bpal. Both shortages, in effective antibiotics and unexplored targets, are even more glaring in the field of non-tuberculous mycobacterial (NTM) diseases which are on a rise and are recognized now as an emerging global threat in both immunocompromised and immunocompetent individuals. Mycobacterial lipoamide dehydrogenase (LPD) represents one of the unexplored but MTB-validated targets and serves in at least 4 enzyme complexes in MTB: in pyruvate dehydrogenase (PDH), -ketoacid dehydrogenase, branched chain keto-acid dehydrogenase, and peroxynitrite reductase/peroxidase. LPD is a genetically validated target: MTB with LPD deleted does not survive in a mouse model of TB infection and a conditionally regulated LPD MTB strain is cleared in mice, when LPD expression is suppressed in either the acute or chronic infection. This application leverages the knowledge of the chemical biology of MTB LPD to explore our newly identified tight binding inhibitors (TBI) of MTB LPD by structure-guided analysis, enzyme kinetics and binding assays to define LPD binding site features responsible for tight binding interactions and extensions of the on-target residence time (T1/2). We aim to define what drives antibacterial activity of LPD TBI, how T1/2 contributes to whole cell activity and selectivity, and how we can design/predict better analogs with improved T1/2 to enable further efficacy improvements. We will develop a framework for progression of tbis from an isolated target to its cellular PDH complex target and its whole cell activity against TB in culture and during host infection. Extension of those studies to NTM pathogens and testing against mycobacterium avium and m. Abscessus LPD orthologs will lead to scaffold progression and SAR development of a novel whole cell active inhibitor of NTM. Collectively our studies will explore the SAR of LPD TBI in vitro, define vulnerability of mycobacterial LPD to chemical inhibition in vivo, advance our understanding of ways to improve inhibitors' efficacy through its target's T1/2, contribute to rational prediction of in vivo efficacy and characterize structural features of mycobacterial PDH that define its distinct macromolecular organization and sustain its functional diversity.
Transactions
| Action | Obligated | Date |
|---|---|---|
| Amendment | $594,241 | |
| Amendment | $576,414 | |
| Amendment | $576,414 | |
| Amendment | $59,424 | |
| Amendment | $59,424 | |
| Amendment | $552,192 | |
| Amendment | $552,192 | |
| Original award | $552,192 |
Subawards
| Subrecipient | Amount | Awarded |
|---|---|---|
| Van Andel Research Institute | $436,240 |
Quick answers
Who received award R01AI175342?
R01AI175342 was awarded to Weill Medical College Of Cornell University by National Institute of Allergy and Infectious Diseases (National Institutes of Health) on November 22, 2023.
How much is award R01AI175342 worth?
$3,522,493 has been obligated on R01AI175342.
On GovTribe
See this award's full record
- Every transaction and subaward
- The recipient's other awards and teaming partners
- Similar grant awards
- Ask GovTribe AI about this award