Venatorx Pharmaceuticals, Inc., 30 Spring Mill Drive, Malvern, Pennsylvania 19355, United States.
Department of Biotechnology, Chemistry and Pharmacy, University of Siena, I-53100 Siena, Italy.
J Med Chem. 2020 Mar 26;63(6):2789-2801. doi: 10.1021/acs.jmedchem.9b01518. Epub 2019 Dec 16.
A major resistance mechanism in Gram-negative bacteria is the production of β-lactamase enzymes. Originally recognized for their ability to hydrolyze penicillins, emergent β-lactamases can now confer resistance to other β-lactam drugs, including both cephalosporins and carbapenems. The emergence and global spread of β-lactamase-producing multi-drug-resistant "superbugs" has caused increased alarm within the medical community due to the high mortality rate associated with these difficult-to-treat bacterial infections. To address this unmet medical need, we initiated an iterative program combining medicinal chemistry, structural biology, biochemical testing, and microbiological profiling to identify broad-spectrum inhibitors of both serine- and metallo-β-lactamase enzymes. Lead optimization, beginning with narrower-spectrum, weakly active compounds, provided (VNRX-5133, taniborbactam), a boronic-acid-containing pan-spectrum β-lactamase inhibitor. In vitro and in vivo studies demonstrated that restored the activity of β-lactam antibiotics against carbapenem-resistant and carbapenem-resistant Enterobacteriaceae. Taniborbactam is the first pan-spectrum β-lactamase inhibitor to enter clinical development.
革兰氏阴性菌的主要耐药机制是产生β-内酰胺酶。最初，β-内酰胺酶因其能够水解青霉素而被识别，但新兴的β-内酰胺酶现在可以对其他β-内酰胺类药物（包括头孢菌素类和碳青霉烯类）产生耐药性。产生和全球传播的产β-内酰胺酶的多药耐药“超级细菌”引起了医学界的高度警惕，因为这些难以治疗的细菌感染与高死亡率有关。为了解决这一未满足的医疗需求，我们启动了一个迭代项目，结合药物化学、结构生物学、生化测试和微生物分析，以确定广谱抑制剂对丝氨酸和金属β-内酰胺酶的抑制作用。从具有较窄谱、较弱活性的化合物开始进行的先导化合物优化，提供了含有硼酸的泛谱β-内酰胺酶抑制剂（VNRX-5133，taniborbactam）。体外和体内研究表明，taniborbactam 恢复了β-内酰胺类抗生素对碳青霉烯类耐药和碳青霉烯类耐药肠杆菌科的活性。Taniborbactam 是第一个进入临床开发的泛谱β-内酰胺酶抑制剂。
