Burkholderia multivorans is a significant health threat to persons with cystic fibrosis (CF). Infections are difficult to treat as this pathogen is inherently resistant to multiple antibiotics. Susceptibility testing of isolates obtained from CF respiratory cultures revealed that single agents selected from different antibiotic classes were unable to inhibit growth. However, all isolates were found to be susceptible to ceftazidime when combined with the novel non-β-lactam β-lactamase inhibitor, avibactam (all minimum inhibitor concentrations (MICs) were ≤8 mg/L of ceftazidime and 4 mg/L of avibactam). Furthermore, a major β-lactam resistance determinant expressed in B. multivorans, the class A carbapenemase, PenA was readily inhibited by avibactam with a high k₂/K of (2 ± 1) × 10⁶ μM^–1 s^–1 and a slow k_off of (2 ± 1) × 10^–3 s^–1. Mass spectrometry revealed that avibactam formed a stable complex with PenA for up to 24 h and that avibactam recyclized off of PenA, re-forming the active compound. Crystallographic analysis of PenA–avibactam revealed several interactions that stabilized the acyl–enzyme complex. The deacylation water molecule possessed decreased nucleophilicity, preventing decarbamylation. In addition, the hydrogen-bonding interactions with Lys-73 were suggestive of a protonated state. Thus, Lys-73 was unlikely to abstract a proton from Ser-130 to initiate recyclization. Using Galleria mellonella larvae as a model for infection, ceftazidime–avibactam was shown to significantly (p < 0.001) improve survival of larvae infected with B. multivorans. To further support the translational impact, the ceftazidime–avibactam combination was evaluated using susceptibility testing against other strains of Burkholderia spp. that commonly infect individuals with CF, and 90% of the isolates were susceptible to the combination. In summary, ceftazidime–avibactam may serve as a preferred therapy for people that have CF and develop Burkholderia spp. infections and should be considered for clinical trials.

中文翻译：

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克服极端耐药性（XDR）病原体：阿维巴坦恢复囊性纤维化患者伯克霍尔德菌洋葱复合体分离物对头孢他啶的敏感性

伯克霍尔德氏菌对囊性纤维化（CF）患者的健康构成重大威胁。感染难以治疗，因为这种病原体固有地对多种抗生素具有抗性。从CF呼吸培养物中分离得到的药敏试验表明，选自不同抗生素类别的单一药物不能抑制其生长。但是，发现与新的非β-内酰胺β-内酰胺酶抑制剂阿维巴坦联合使用时，所有分离株均对头孢他啶敏感（所有最小抑制剂浓度（MIC）均≤8mg / L头孢他啶和4 mg / L avibactam ）。此外，在表达的主要β内酰胺抗性决定B. multivorans，A类碳青霉烯酶，尼亚被容易地通过avibactam具有高抑制ķ ₂/ ķ（2±1）×10 ⁶ μM ^-1小号^-1和慢ķ_关闭的（2±1）×10 ^-3小号^-1。质谱分析表明，avibactam与PenA形成稳定的复合物长达24小时，avibactam从PenA中循环出来，重新形成了活性化合物。PenA-avibactam的晶体学分析表明，有几种相互作用可以稳定酰基-酶复合物。脱酰水分子具有降低的亲核性，从而防止了脱氨甲酰化。此外，与Lys-73的氢键相互作用表明存在质子化状态。因此，Lys-73不太可能从Ser-130提取质子来启动再循环。使用盖勒幼虫幼虫作为感染的模型，头孢他啶-avibactam被证明可以显着（p <0.001）提高感染多食双歧杆菌的幼虫的存活率。为了进一步支持翻译影响，使用对Burkholderia spp其他菌株的药敏试验评估了头孢他啶-avibactam的组合。通常会感染CF，并且90％的分离株容易受到该组合的影响。总之，头孢他啶-avibactam可能是患有CF并发展Burkholderia spp的人的首选治疗方法。感染，应考虑用于临床试验。