Optimization of atypical antimycobacterial carbapenem antibiotics
Active Project Grant Awarded Last action
- Award ID
- R01AI174599
- Recipient
-
Southern Methodist University UEI D33QGS3Q3DJ3
- Awarding agency
-
National Institute of Allergy and Infectious Diseases
National Institutes of Health, Department of Health and Human Services
- Obligated
- $2,812,818
Award facts
- Assistance listing
- 93.855 Allergy and Infectious Diseases Research
- Completion date 66% complete
- Place of performance
- Dallas, TX 75205, USA
Award details come from USAspending.gov.
Description
- Abstract
- Mycobacterial infections, broadly including mycobacterium tuberculosis (MTB), and those caused by nontuberculous mycobacteria (NTM) like the fast-growing mycobacterium abscessus (MAB), as well as the slow- growing mycobacterium avium complex (MAC), represent some of the most clinically challenging and deadly infections of the 21ST century. Treatments typically involve regimens of multiple antibiotics that are administered for lengthy periods of time, and poor outcomes are common. -lactam antibiotics have not traditionally been a part of these treatment regimens, due to -lactamase mediated resistance, and because some classes of - lactams lack antimycobacterial activity. Significantly, for peptidoglycan crosslinking, mycobacterial species primarily use an alternate L, D-transpeptidase (LDT) in place of the canonical D, D-transpeptidase (DDT) (or penicillin binding protein, PBP), the latter of which is the primary target of typically administered -lactams. Ldts and ddts are nonhomologous proteins which, in part, explains the apparent ineffectiveness of this drug class against mycobacterial species. This application involves design and synthesis of carbapenem antibiotics with substantial and unusual (ATYPICAL) structural alterations, in contrast to existing agents which differ only at the C2 position. Previously, we have demonstrated that these scaffold modifications can improve activity against gram- negative pathogens, minimize efflux, and improve resistance to -lactamase-mediated hydrolysis. Preliminary studies for this project yielded an ATYPICAL carbapenem with superior potency compared to commercially available carbapenems against diverse MTB and MAB clinical isolates. Unlike meropenem, this new ATYPICAL carbapenem maintained its potency against resistant mycobacterial pathogens in the absence of a combination -lactamase inhibitor, displaying up to 20-fold improvements over meropenem in activity against these resistant strains. Its excellent, broad spectrum antimycobacterial potency (mics < 1 G/ML) was not diminished by carbapenemase producing mycobacterial species nor was activity further improved by combination with -lactamase inhibitors thus indicating -lactamase stability. Activity was also assessed against a diverse panel of nonmycobacterial species indicating the new antibiotic is beginning to demonstrate selectivity for the mycobacteria genus over other gram-negative and gram-positive species. We now plan to develop this initial discovery into an orally bioavailable clinically useful antimycobacterial agent and to further improve the antimycobacterial potency and specificity of this unique ATYPICAL carbapenem. Stability to carbapenemases will be an asset in an orally bioavailable agent since many carbapenemase inhibitors (e.g. avibactam) are not orally bioavailable. The scientific operations are guided by a highly qualified team including synthesis, microbiology, biochemistry, and structural biology. A thorough and rigorous array of analyses, including numerous in vitro and in vivo PK evaluations, will guide development.
Transactions
| Action | Obligated | Date |
|---|---|---|
| Amendment | $673,531 | |
| Amendment | $681,269 | |
| Amendment | $0 | |
| Amendment | $698,616 | |
| Original award | $759,402 |
Subawards
| Subrecipient | Amount | Awarded |
|---|---|---|
| The University Of Kentucky Research Foundation | $126,925 | |
| The University Of Central Florida Board Of Trustees | $250,627 | |
| The University Of Central Florida Board Of Trustees | $52,011 | |
| The University Of Kentucky Research Foundation | $128,084 | |
| The University Of Central Florida Board Of Trustees | $224,960 | |
| The University Of Central Florida Board Of Trustees | $224,960 | |
| The University Of Kentucky Research Foundation | $74,598 |
Quick answers
Who received award R01AI174599?
R01AI174599 was awarded to Southern Methodist University by National Institute of Allergy and Infectious Diseases (National Institutes of Health) on July 19, 2023.
How much is award R01AI174599 worth?
$2,812,818 has been obligated on R01AI174599.
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