The Class A β-Lactamase Produced by Burkholderia Species Compromises the Potency of Tebipenem against a Panel of Isolates from the United States.
The Class A β-Lactamase Produced by Burkholderia Species Compromises the Potency of Tebipenem against a Panel of Isolates from the United States.
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DOI：
10.3390/antibiotics11050674
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发表时间：
2022-05-17
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影响因子：
--
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中科院分区：
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Tebipenem-pivoxil Hydrobromide 是一种口服生物可利用的碳青霉烯类药物，目前正处于临床开发阶段，用于治疗产生超广谱 β-内酰胺酶和 AmpC 的肠杆菌。此前，替比培南被发现对生物威胁病原体、类鼻疽伯克霍尔德氏菌和鼻疽伯克霍尔德氏菌具有抗菌活性。因此，本文对替比培南针对 150 种洋葱伯克霍尔德菌复合体 (Bcc) 和唐菖蒲伯克霍尔德菌（感染免疫功能低下或患有囊性纤维化的人的病原体）的一组进行了评估。使用替比培南 0.12 mg/L 的临时敏感性断点，100% 的 Bcc 和剑兰被测试为对替比培南具有临时耐药性。 Bcc 和剑兰拥有两种诱导型染色体 β-内酰胺酶：PenA 和 AmpC。使用纯化的 PenA1 和 AmpC1（在伯克霍尔德氏菌 ATCC 17616 中表达的模型 β-内酰胺酶），发现 PenA1 会缓慢水解替比培南，而 AmpC1 会被替比培南抑制，k2/K 值为 1.9 ± 0.1 × 103 M−1s−1。此外，发现替比培南是 blaPenA1 表达的弱诱导剂。 PenA1 的缓慢水解和 blaPenA1 的弱诱导相结合可能会损害替比培南对抗 Bcc 和剑兰的效力。
Tebipenem-pivoxil hydrobromide, an orally bioavailable carbapenem, is currently in clinical development for the treatment of extended-spectrum β-lactamase- and AmpC-producing Enterobacterales. Previously, tebipenem was found to possess antimicrobial activity against the biothreat pathogens, Burkholderia pseudomallei and Burkholderia mallei. Thus, herein, tebipenem was evaluated against a panel of 150 curated strains of Burkholderia cepacia complex (Bcc) and Burkholderia gladioli, pathogens that infect people who are immunocompromised or have cystic fibrosis. Using the provisional susceptibility breakpoint of 0.12 mg/L for tebipenem, 100% of the Bcc and B. gladioli tested as being provisionally resistant to tebipenem. Bcc and B. gladioli possess two inducible chromosomal β-lactamases, PenA and AmpC. Using purified PenA1 and AmpC1, model β-lactamases expressed in Burkholderia multivorans ATCC 17616, PenA1 was found to slowly hydrolyze tebipenem, while AmpC1 was inhibited by tebipenem with a k2/K value of 1.9 ± 0.1 × 103 M−1s−1. In addition, tebipenem was found to be a weak inducer of blaPenA1 expression. The combination of the slow hydrolysis by PenA1 and weak induction of blaPenA1 likely compromises the potency of tebipenem against Bcc and B. gladioli.
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作者：
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