Structural determinants of activity and mechanism of cationic peptide antibiotic activity against colistin-resistant bacteria
Active Project Grant Awarded Last action
- Award ID
- R01AI172861
- Recipient
-
University Of Pittsburgh - Of The Commonwealth System Of Higher Education UEI MKAGLD59JRL1
- Awarding agency
-
National Institute of Allergy and Infectious Diseases
National Institutes of Health, Department of Health and Human Services
- Obligated
- $3,813,430
Award facts
- Assistance listing
- 93.855 Allergy and Infectious Diseases Research
- Completion date 68% complete
- Place of performance
- Pittsburgh, PA 15222, USA
Award details come from USAspending.gov.
Description
- Abstract
- The emergence of antibiotic resistance (AR) underscores the urgent need to develop novel antimicrobial agents that are able to overcome current AR mechanisms. Antimicrobial peptides (amps) tend to disrupt bacterial membranes regardless of resistance to traditional antibiotics. However, bacteria have also evolved to resist the effects of amps by reducing (e.g., incorporation of phosphoethanolamine), not eliminating, the net electronegative charge of lipid a, an important component of LPS targeted by amps. Because a minimum electronegative charge is essential to bacterial membrane integrity, amps can be optimized to overcome limited changes in LPS, the most common resistance mechanism against endogenous amps and colistin. We have developed an iterative framework for rational design of engineered cationic peptide antibiotics (PAX) optimized for broad activity against multidrug-resistant (MDR) bacteria. We used libraries of rationally designed series of novel TRP-rich peptides differing by 2 residues at a time, 1 VAL and 1 ARG to establish the distinction between structural determinants of antimicrobial potency and those of host toxicity. As predicted, lowest minimum inhibitory concentrations (MIC) are achieved against MDR clinical isolates without substantial increase in red blood cell lysis or toxicity to white blood cells at maximum test concentrations. Remarkably, one of the selected PAX (E35) demonstrates efficacy when systemically administered at 4-5MG/KG either a single dose (MDR p. Aeruginosa infection) or multiple doses (MDR klebsiella pneumonia infection) in mice. PAX E35 also displayed a maximum tolerated dose of 30 MG/KG compared to 12-15 MG/KG of our initial lead peptide WLBU2 now in phase 2 clinical trial. Our iterative framework minimizes trial and error for designing PAX with enhanced systemic efficacy against MDR bacteria. Given the success against colistin-resistant (COL-r) bacteria, the tendency is to claim that our work is done without thinking of potential shortcomings of the current PAX. However, there are still too many unknowns. (1) MDR bacteria have not been exposed clinically to the peptides as they have been to colistin. Once they do, IT is almost certain that resistance frequency will steadily increase. (2) the current structural optimization is only minimal because we have not yet determined how each of the cationic (c) and hydrophobic (h) motifs contributes to bacterial recognition and killing. Thus, IT is critical to continue this important work while some of the PAX may progress to advanced pre-clinical and clinical studies. We propose to define the contribution of the 2 motifs to target recognition and elimination using COL-r strains that can be passaged to evolve resistance to the current PAX. The overarching goal of this proposal is to elucidate the molecular determinants for bacterial resistance to PAX by uncoupling the c and h motifs of PAX to allow c/h correlation with changes in LPS structures and corresponding bactericidal activity using both COL-r and PAX-r MDR clinical isolates. Impact: we will progress from a minimal one-drug to a comprehensive one- therapeutic class approach with the ability to design or RE-design PAX based on clinical challenges.
Transactions
| Action | Obligated | Date |
|---|---|---|
| Amendment | $626,415 | |
| Amendment | $626,415 | |
| Amendment | $626,415 | |
| Amendment | $626,415 | |
| Amendment | $653,885 | |
| Original award | $653,885 |
Subawards
| Subrecipient | Amount | Awarded |
|---|---|---|
| University Of Maryland, Baltimore | $154,500 | |
| Carnegie Mellon University | $76,100 | |
| Carnegie-Mellon University | $38,050 | |
| University Of Maryland, Baltimore | $62,687 |
Quick answers
Who received award R01AI172861?
R01AI172861 was awarded to University Of Pittsburgh - Of The Commonwealth System Of Higher Education by National Institute of Allergy and Infectious Diseases (National Institutes of Health) on June 1, 2023.
How much is award R01AI172861 worth?
$3,813,430 has been obligated on R01AI172861.
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