The Next-Generation β-Lactamase Inhibitor Taniborbactam Restores the Morphological Effects of Cefepime in KPC-Producing Escherichia coli.
The Next-Generation β-Lactamase Inhibitor Taniborbactam Restores the Morphological Effects of Cefepime in KPC-Producing Escherichia coli.
复制标题
新一代β-内酰胺酶抑制剂Taniborbactam可恢复头孢吡肟对产KPC大肠杆菌的形态学影响。
DOI：
10.1128/spectrum.00918-21
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发表时间：
2021-10-31
影响因子：
3.7
通讯作者：
Khursigara CM
中科院分区：
文献类型：
--
作者：
Roach EJ;Uehara T;Daigle DM;Six DA;Khursigara CM
产碳青霉烯酶的革兰氏阴性菌对多种β-内酰胺类抗生素具有耐药性，并造成重大健康风险。由于缺乏新的抗生素，新的广谱β-内酰胺酶抑制剂（BLI）与批准的β-内酰胺类药物的组合为耐药细菌感染提供了治疗选择。Taniborbactam（以前称为VNRX-5133）是一种研究性BLI，对丝氨酸和金属β-内酰胺酶（包括丝氨酸碳青霉烯酶KPC）均有效。在本研究中，我们评估了他尼博巴坦通过抑制头孢吡肟的KPC-3依赖性水解来恢复头孢吡肟对产KPC-3大肠杆菌的抗菌活性的有效性。延时显微镜显示，用大于1× MIC的头孢吡肟（128 μg/ml）和头孢吡肟-他尼博巴坦（4 μg/ml头孢吡肟和4 μg/ml他尼博巴坦）处理的细胞表现出显著的延长，而单独用他尼博巴坦处理的细胞则没有，这是因为BLI缺乏独立的抗菌活性。伸长的细胞也有频繁的细胞空隙，认为是由细胞分裂和细胞质膜挤压形成的。此外，甚至在从生长培养基中去除他尼博巴坦后，其作用仍持续。用4 μg/ml的他尼博巴坦预处理有助于通过中和KPC-3 β-内酰胺酶的作用恢复头孢吡肟的抗菌作用。重要性β-内酰胺（BL）抗生素是最常用的抗菌药物。β-内酰胺类药物的疗效受到β-内酰胺酶的产生的威胁，β-内酰胺酶是革兰氏阴性细菌病原体中影响这些药物的主要耐药机制。本研究观察了他尼博巴坦（一种广谱β-内酰胺酶抑制剂（BLI））和BL抗生素头孢吡肟联合治疗对产碳青霉烯酶大肠杆菌的影响。coli菌株。虽然这种治疗已经在其他头孢菌素耐药菌的背景下进行了描述，但这是第一次描述对产KPC-3的大肠杆菌菌株进行显微镜评价。大肠杆菌的攻击。用他尼博巴坦和头孢吡肟处理的细胞的活细胞显微镜分析证明了对细胞形态的抗微生物作用，并强调了即使在从培养基中除去后，他尼博巴坦对β-内酰胺酶的持久抑制作用。这项研究说明了taniborbactam在对抗BL介导的抗生素耐药性方面的重要性。
Gram-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.