smith-et-al-2023-the-c5α-methyl-substituted-carbapenem-na-1-157-exhibits-potent-activity-against-klebsiella-spp

C5α-Methyl-Substituted Carbapenem NA-1-157
- Promising candidate for treating infections caused by Klebsiella spp.
- Exhibits potent activity against isolates producing OXA-48-type carbapenemases.

Challenge in Antibiotic Resistance
- Carbapenem-hydrolyzing β-lactamases have reduced effectiveness of carbapenems, critical last-resort antibiotics.
- OXA-48-type β-lactamases are a major mechanism of resistance in Enterobacteriaceae, especially K. pneumoniae and E. coli.
- Development of novel therapeutics is necessary to combat resistance.

Potency Compared to Other Carbapenems
- NA-1-157 shows 4- to 32-fold reduced MICs against OXA-48-producing bacteria compared to meropenem.
- When combined with commercial carbapenems, NA-1-157 enhances their activity, with TPCs ranging from 0.125 to 2 µg/mL.

Kinetic Properties
- Poorly hydrolyzed by OXA-48 compared to imipenem and meropenem (30- to 50-fold lower catalytic efficiency).
- Acylation of OXA-48 by NA-1-157 is significantly impaired (10,000- to 36,000-fold slower).
Structural Insights
- C5α-methyl group introduces steric clashes in the active site of OXA-48, altering hydrogen-bonding patterns.
- Docking studies illustrate positioning differences that hinder efficient acylation compared to meropenem.

Public Health Impact
- Infections with carbapenem-resistant bacteria lead to long hospital stays, increased healthcare costs, and high mortality rates (70%-80%).
- Resistance mechanisms include altered drug targets, decreased drug uptake, and enhanced efflux.
Need for Novel Inhibitors
- Focus on designing non-β-lactam inhibitors and modifying existing scaffolds for improved efficacy.

Efficacy of NA-1-157
- Demonstrated strong antimicrobial activity against OXA-48-producing bacteria.
- Highlights potential of carbapenem modifications as a strategy for developing effective treatments against resistant bacteria.