Developing prodrugs to selectively suppress beta-lactam resistant bacteria
Active Project Grant Awarded Last action
- Award ID
- F31AI200226
- Recipient
-
Duke University UEI TP7EK8DZV6N5
- Awarding agency
-
National Institute of Allergy and Infectious Diseases
National Institutes of Health, Department of Health and Human Services
- Obligated
- $87,250
Award facts
- Assistance listing
- 93.855 Allergy and Infectious Diseases Research
- Completion date 0% complete
- Originally
- Place of performance
- Durham, NC 27708, USA
Award details come from USAspending.gov.
Description
- Abstract
- Bacterial infections pose an escalating global health threat due to the rapid spread of antibiotic resistance. Β- lactam antibiotics, which target penicillin-binding proteins (pbps) to disrupt bacterial cell wall synthesis, remain the most widely used class of antibiotics in clinical practice. However, widespread β-lactam use has led to the emergence of β-lactamase (BL)-producing bacterial strains that inactivate these drugs, severely limiting treatment options. BLS are easily transferred among bacteria via horizontal gene transfer, accelerating the resistance crisis. Although BL inhibitors can partially restore antibiotic activity when CO-administered with β- lactams, they often lack specificity and disrupt the host microbiome. Moreover, the molecular features that govern selective β-lactam recognition by pbps versus BLS remain poorly understood, hindering the rational design of targeted therapeutics. This project seeks to address these challenges by developing β-lactam prodrugs that are selectively activated by BLS in resistant bacteria. I hypothesize that strategic modifications to the β-lactam scaffold can enable selective hydrolysis by BLS while minimizing interaction with pbps. To test this, i will employ a high-throughput, fragment-based drug design approach to synthesize β-lactam prodrugs, which i will then evaluate for their biochemical and microbiological properties. Enzymatic assays and structure-activity relationship studies will define the scaffold features that drive selective BL activation. Promising candidates will be tested in bacterial CO-culture models to assess whether selective activation suppresses resistant strains while sparing sensitive ones. By harnessing resistance for selective drug activation, this work aims to establish a new therapeutic paradigm. Ultimately, this approach could lead to the development of next-generation β-lactam antibiotics that selectively target resistant pathogens while preserving the beneficial microbiota, helping to combat the global threat of multidrug resistance.
Transactions
| Action | Obligated | Date |
|---|---|---|
| Amendment | $43,625 | |
| Amendment | $0 | |
| Original award | $43,625 |
Quick answers
Who received award F31AI200226?
F31AI200226 was awarded to Duke University by National Institute of Allergy and Infectious Diseases (National Institutes of Health) on November 23, 2026.
How much is award F31AI200226 worth?
$87,250 has been obligated on F31AI200226.
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