迫切需要口服药剂来对抗抗性革兰氏阴性病原体。这里,我们描述了VNRX-5236,广谱硼酸β-内酰胺酶抑制剂(BLI),及其口服生物可利用的etzadroxil前药,VNRX-7145。VNRX-7145正在与头孢替丁联合开发,口服头孢菌素,对抗表达超广谱β-内酰胺酶(ESBLs)和丝氨酸碳青霉烯酶的肠杆菌菌株。VNRX-5236是丝氨酸β-内酰胺酶的可逆共价抑制剂,失活效率约为104M-1·sec-1,活性位点停留时间延长(t1/2,5至46分钟)。抑制谱包括AmblerA类ESBLs,C类头孢菌素酶,以及A类和D类碳青霉烯酶(分别为KPC和OXA-48)。用VNRX-5236(固定为4μg/ml)在表达A类的大肠杆菌等基因菌株中挽救头孢替丁,C,或Dβ-内酰胺酶表现出相对于口服比较物的扩大的活性谱,包括研究性的penems,sulopenem,还有Tebipenem.VNRX-5236在表达ESBLs(MIC90,0.25μg/ml)的肠杆菌临床分离株中挽救了头孢替丁的活性,KPCs(MIC90,1μg/ml),C类头孢菌素酶(MIC90,1μg/ml),和OX-48型碳青霉烯酶(MIC90,1μg/ml)。抗性研究的频率表明,在头孢替布汀/VNRX-5236组合的4倍MIC时,抗性变体的恢复倾向较低。在体内,而单用头孢替丁无效(50%有效剂量[ED50],>128mg/kg),头孢替丁/VNRX-7145口服保护小鼠免受肺炎克雷伯菌引起的致命性败血症产生KPC碳青霉烯酶(ED50,12.9mg/kg)。数据显示有效,VNRX-5236在头孢菌素耐药和碳青霉烯耐药肠杆菌临床分离株中对头孢替丁活性的广谱抢救。
There is an urgent need for oral agents to combat resistant Gram-negative pathogens. Here, we describe the characterization of VNRX-5236, a broad-spectrum boronic acid β-lactamase inhibitor (BLI), and its orally bioavailable etzadroxil prodrug, VNRX-7145. VNRX-7145 is being developed in combination with ceftibuten, an oral cephalosporin, to combat strains of Enterobacterales expressing extended-spectrum β-lactamases (ESBLs) and serine carbapenemases. VNRX-5236 is a reversible covalent inhibitor of serine β-lactamases, with inactivation efficiencies on the order of 104 M-1 · sec-1, and prolonged active site residence times (t1/2, 5 to 46 min). The spectrum of inhibition includes Ambler class A ESBLs, class C cephalosporinases, and class A and D carbapenemases (KPC and OXA-48, respectively). Rescue of ceftibuten by VNRX-5236 (fixed at 4 μg/ml) in isogenic strains of Escherichia coli expressing class A, C, or D β-lactamases demonstrated an expanded spectrum of activity relative to oral comparators, including investigational penems, sulopenem, and tebipenem. VNRX-5236 rescued ceftibuten activity in clinical isolates of Enterobacterales expressing ESBLs (MIC90, 0.25 μg/ml), KPCs (MIC90, 1 μg/ml), class C cephalosporinases (MIC90, 1 μg/ml), and OXA-48-type carbapenemases (MIC90, 1 μg/ml). Frequency of resistance studies demonstrated a low propensity for recovery of resistant variants at 4× the MIC of the ceftibuten/VNRX-5236 combination. In vivo, whereas ceftibuten alone was ineffective (50% effective dose [ED50], >128 mg/kg), ceftibuten/VNRX-7145 administered orally protected mice from lethal septicemia caused by Klebsiella pneumoniae producing KPC carbapenemase (ED50, 12.9 mg/kg). The data demonstrate potent, broad-spectrum rescue of ceftibuten activity by VNRX-5236 in clinical isolates of cephalosporin-resistant and carbapenem-resistant Enterobacterales.