Synthesis and Preclinical Evaluation of TPA-Based Zinc Chelators as Metallo-β-lactamase Inhibitors.,ACS Infectious Diseases

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Synthesis and Preclinical Evaluation of TPA-Based Zinc Chelators as Metallo-β-lactamase Inhibitors.
ACS Infectious Diseases ( IF 4.0 ) Pub Date : 2018-08-02 , DOI: 10.1021/acsinfecdis.8b00137
Christian Schnaars , Geir Kildahl-Andersen , Anthony Prandina ₁ , Roya Popal , Sylvie Radix ₁ , Marc Le Borgne ₁ , Tor Gjøen , Adriana Magalhães Santos Andresen , Adam Heikal ₂ , Ole Andreas Økstad ₂ , Christopher Fröhlich _{3,

4} , Ørjan Samuelsen _{3,

5} , Silje Lauksund ₃ , Lars Petter Jordheim ₆ , Pål Rongved , Ove Alexander Høgmoen Åstrand

Affiliation

The rise of antimicrobial resistance (AMR) worldwide and the increasing spread of multi-drug-resistant organisms expressing metallo-β-lactamases (MBL) require the development of efficient and clinically available MBL inhibitors. At present, no such inhibitor is available, and research is urgently needed to advance this field. We report herein the development, synthesis, and biological evaluation of chemical compounds based on the selective zinc chelator tris-picolylamine (TPA) that can restore the bactericidal activity of Meropenem (MEM) against Pseudomonas aeruginosa and Klebsiella pneumoniae expressing carbapenemases Verona integron-encoded metallo-β-lactamase (VIM-2) and New Delhi metallo-β-lactamase 1 (NDM-1), respectively. These adjuvants were prepared via standard chemical methods and evaluated in biological assays for potentiation of MEM against bacteria and toxicity (IC50) against HepG2 human liver carcinoma cells. One of the best compounds, 15, lowered the minimum inhibitory concentration (MIC) of MEM by a factor of 32-256 at 50 μM within all tested MBL-expressing clinical isolates and showed no activity toward serine carbapenemase expressing isolates. Biochemical assays with purified VIM-2 and NDM-1 and 15 resulted in inhibition kinetics with kinact/ KI of 12.5 min-1 mM-1 and 0.500 min-1 mM-1, respectively. The resistance frequency of 15 at 50 μM was in the range of 10-7 to 10-9. 15 showed good tolerance in HepG2 cells with an IC50 well above 100 μM, and an in vivo study in mice showed no acute toxic effects even at a dose of 128 mg/kg.

中文翻译：

基于TPA的锌螯合剂作为金属β-内酰胺酶抑制剂的合成及临床前评价。

全球抗菌素耐药性（AMR）的兴起和表达金属β-内酰胺酶（MBL）的多药耐药生物的日益普及，要求开发有效且临床上可用的MBL抑制剂。目前，尚无此类抑制剂，因此迫切需要研究以促进该领域的发展。我们在此报告了基于选择性锌螯合剂三甲基吡啶胺（TPA）的化合物的开发，合成和生物学评估，该化合物可恢复美罗培南（MEM）对铜绿假单胞菌和肺炎克雷伯菌表达碳青霉烯酶维罗纳整合子编码金属的杀菌活性-β-内酰胺酶（VIM-2）和新德里金属-β-内酰胺酶1（NDM-1）。这些佐剂是通过标准化学方法制备的，并在生物学分析中评估了MEM对细菌的增强作用以及对HepG2人肝癌细胞的毒性（IC50）。最佳化合物之一15在所有测试的表达MBL的临床分离株中以50μM的浓度将MEM的最低抑菌浓度（MIC）降低了32-256倍，并且对表达丝氨酸碳青霉烯酶的分离株无活性。用纯化的VIM-2和NDM-1和15进行生化分析可得出抑制动力学，其kinact / KI分别为12.5 min-1 mM-1和0.500 min-1 mM-1。50μM时15的电阻频率在10-7至10-9的范围内。图15在HepG2细胞中表现出良好的耐受性，IC50远高于100μM，并且在小鼠体内的研究显示，即使以128 mg / kg的剂量使用，也没有急性毒性作用。

更新日期：2018-07-19

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