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Published on: October 17, 2019
Spectrum of cefepime-taniborbactam coverage against 190 β-lactamases defined in engineered isogenic Escherichia coli
Tsuyoshi Uehara1, Cassandra L Chatwin1, Brittany Miller1
1Venatorx Pharmaceuticals Inc, Malvern, Pennsylvania, USA.
Abstract:
Cefepime-taniborbactam is a β-lactam/β-lactamase inhibitor combination in clinical development for the treatment of Enterobacterales and Pseudomonas infections, including carbapenem-resistant Enterobacterales and multidrug-resistant Pseudomonas aeruginosa. Taniborbactam is a novel cyclic boronate with direct inhibitory activity against clinically relevant Ambler class A, B, C, and D β-lactamases. To further characterize the spectrum of β-lactamase coverage by cefepime-taniborbactam, we constructed 190 isogenic strains of Escherichia coli that constitutively expressed a different β-lactamase. Synthetic codon-optimized genes encoding the mature periplasmic protein linked to the TEM-1 signal sequence were used for optimized expression and periplasmic localization of the β-lactamase. The repertoire of β-lactamases consisted of 50 Ambler class A, 34 class B (metallo), 48 class C, and 58 class D enzymes known to mediate β-lactam resistance in the clinical isolates of Enterobacterales and P. aeruginosa. Overall, in the 190 isogenic strains, the MIC50/MIC90 values were 8/128 µg/mL for cefepime and >128/>128 µg/mL for ceftazidime. Cefepime-taniborbactam (MIC50/MIC90 of 0.25/8 µg/mL) showed greater activity than ceftazidime-avibactam (MIC50/MIC90 of 4/>128 µg/mL) and similar activity to aztreonam-avibactam (MIC50/MIC90 of 0.5/4 µg/mL). Cefepime-taniborbactam inhibited strains overproducing metallo-β-lactamases, including clinically important NDM and VIM enzymes, whereas ceftazidime-avibactam showed no coverage. Among the 129 β-lactamase-overproducing strains with increased cefepime MIC ≥16-fold relative to the control strain, taniborbactam potentiated cefepime MIC by ≥8-fold for 113 strains overexpressing β-lactamases (42 Ambler class A, 24 B, 23 C, and 24 D). Cefepime-taniborbactam demonstrated broader activity relative to ceftazidime-avibactam and comparable activity with aztreonam-avibactam in the overall coverage of both serine- and metallo-β-lactamases from all four Ambler classes.
Insights
Cefepime-taniborbactam effectively treats infections caused by resistant bacteria, including metallo-β-lactamase producers. This novel combination shows broad-spectrum activity against challenging Enterobacterales and Pseudomonas aeruginosa infections.
Area of Science:
- Microbiology
- Pharmacology
- Infectious Diseases
Background:
- Antibiotic resistance, particularly from β-lactamase enzymes, poses a significant threat to treating Enterobacterales and Pseudomonas infections.
- Cefepime-taniborbactam is a novel combination therapy targeting these resistant pathogens.
- Taniborbactam is a cyclic boronate inhibitor effective against Ambler class A, B, C, and D β-lactamases.
Purpose of the Study:
- To evaluate the in vitro activity of cefepime-taniborbactam against a wide range of β-lactamase-producing bacterial strains.
- To compare the efficacy of cefepime-taniborbactam with other relevant antibiotic combinations, such as ceftazidime-avibactam and aztreonam-avibactam.
Main Methods:
- 190 isogenic Escherichia coli strains were constructed, each constitutively expressing a different β-lactamase from Ambler classes A, B, C, and D.
- Synthetic, codon-optimized genes encoding mature periplasmic proteins with TEM-1 signal sequences were used for expression.
- Minimum Inhibitory Concentrations (MICs) were determined for cefepime-taniborbactam, ceftazidime-avibactam, and aztreonam-avibactam.
Main Results:
- Cefepime-taniborbactam demonstrated potent activity (MIC50/MIC90: 0.25/8 µg/mL) against a broad spectrum of β-lactamases, including metallo-β-lactamases (e.g., NDM, VIM).
- It showed superior activity compared to ceftazidime-avibactam (MIC50/MIC90: 4/>128 µg/mL) and comparable activity to aztreonam-avibactam (MIC50/MIC90: 0.5/4 µg/mL).
- Taniborbactam potentiated cefepime activity against 113 of 129 strains with high-level cefepime resistance due to β-lactamase overexpression.
Conclusions:
- Cefepime-taniborbactam exhibits broad-spectrum activity against serine and metallo-β-lactamases from all four Ambler classes.
- This combination represents a promising therapeutic option for infections caused by multidrug-resistant Enterobacterales and Pseudomonas aeruginosa.
- Its efficacy against metallo-β-lactamase producers offers a critical advantage over existing therapies like ceftazidime-avibactam.
