Abstract
ABSTRACTGram-negative bacteria producing carbapenemases are resistant to a variety of β-lactam antibiotics and pose a significant health risk. Given the dearth of new antibiotics, combinations of new broad-spectrum β-lactamase inhibitors (BLIs) with approved β-lactams have provided treatment options for resistant bacterial infections. Taniborbactam (formerly VNRX-5133) is an investigational BLI that is effective against both serine- and metallo-β-lactamases, including the serine carbapenemase KPC. In the current study, we assessed the effectiveness of taniborbactam to restore antibacterial activity of cefepime against KPC-3-producing Escherichia coli by inhibiting the KPC-3-dependent hydrolysis of cefepime. Time-lapse microscopy revealed that cells treated with greater than 1× MIC of cefepime (128 μg/ml) and cefepime-taniborbactam (4 μg/ml cefepime and 4 μg/ml taniborbactam) exhibited significant elongation, whereas cells treated with taniborbactam alone did not owing to a lack of standalone antibacterial activity of the BLI. The elongated cells also had frequent cellular voids thought to be formed by attempted cell divisions and pinching of the cytoplasmic membrane. Additionally, the effect of taniborbactam continued even after its removal from the growth medium. Pretreatment with 4 μg/ml taniborbactam helped to restore the antibacterial action of cefepime by neutralizing the effect of the KPC-3 β-lactamase.IMPORTANCE β-lactam (BL) antibiotics are the most prescribed antimicrobial class. The efficacy of β-lactams is threatened by the production of β-lactamase enzymes, the predominant resistance mechanism impacting these agents in Gram-negative bacterial pathogens. This study visualizes the effects of a combination treatment of taniborbactam, a broad spectrum β-lactamase inhibitor (BLI), and the BL antibiotic cefepime on a carbapenemase-producing E. coli strain. While this treatment has been described in the context of other cephalosporin-resistant bacteria, this is the first description of a microscopic evaluation of a KPC-3-producing strain of E. coli challenged by this BL-BLI combination. Live-cell microscopy analysis of cells treated with taniborbactam and cefepime demonstrated the antimicrobial effects on cellular morphology and highlighted the long-lasting inhibition of β-lactamases by taniborbactam even after it was removed from the medium. This research speaks to the importance of taniborbactam in fighting BL-mediated antibiotic resistance.
Highlights
Gram-negative bacteria producing carbapenemases are resistant to a variety of b-lactam antibiotics and pose a significant health risk
Few treatment options remain as the rate of discovery and development of new antibiotics is outpaced by bacterial resistance development [2]
Taniborbactam did not inhibit growth of CDC-0001 even at 128 mg/ml when tested alone, but it did potentiate the antibacterial activity of cefepime to an MIC of 4 mg/ml when tested at a fixed b-lactamase inhibitors (BLIs) concentration of 4 mg/ml
Summary
Gram-negative bacteria producing carbapenemases are resistant to a variety of b-lactam antibiotics and pose a significant health risk. This study visualizes the effects of a combination treatment of taniborbactam, a broad spectrum b-lactamase inhibitor (BLI), and the BL antibiotic cefepime on a carbapenemase-producing E. coli strain. Inhibition of PBP3 effectively halts cross-linking of newly synthesized peptidoglycan polymers at the cell division site while the growing bacterial cell forms long filaments and continues to remodel septal peptidoglycan by hydrolysis for cellular division [9, 10]. This remodeling, in the absence of PBP3 activity, leads to foci of cell wall weakness, cell bulging, and cell lysis [11, 12]. Taniborbactam exhibits reversible covalent inhibition of serine-b-lactamases and competitive inhibition of dizinc active site subclass B1 metallob-lactamases, blocking cefepime hydrolysis and restoring the activity of the b-lactam against MDR Gram-negative bacteria [6, 7]
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