Reck Folkert, Bermingham Alun, Blais Johanne, Capka Vladimir, Cariaga Taryn, Casarez Anthony, Colvin Richard, Dean Charles R, Fekete Alex, Gong Wanben, Growcott Ellie, Guo Hongqiu, Jones Adriana K, Li Cindy, Li Fengxia, Lin Xiaodong, Lindvall Mika, Lopez Sara, McKenney David, Metzger Louis, Moser Heinz E, Prathapam Ramadevi, Rasper Dita, Rudewicz Patrick, Sethuraman Vijay, Shen Xiaoyu, Shaul Jacob, Simmons Robert L, Tashiro Kyuto, Tang Dazhi, Tjandra Meiliana, Turner Nancy, Uehara Tsuyoshi, Vitt Charles, Whitebread Steven, Yifru Aregahegn, Zang Xu, Zhu Qingming
Novartis Institutes for BioMedical Research, Emeryville, CA, USA.
Novartis Institutes for BioMedical Research, Emeryville, CA, USA.
Bioorg Med Chem Lett. 2018 Feb 15;28(4):748-755. doi: 10.1016/j.bmcl.2018.01.006. Epub 2018 Jan 4.
Metallo-β-lactamases (MBLs), such as New Delhi metallo-β-lactamase (NDM-1) have spread world-wide and present a serious threat. Expression of MBLs confers resistance in Gram-negative bacteria to all classes of β-lactam antibiotics, with the exception of monobactams, which are intrinsically stable to MBLs. However, existing first generation monobactam drugs like aztreonam have limited clinical utility against MBL-expressing strains because they are impacted by serine β-lactamases (SBLs), which are often co-expressed in clinical isolates. Here, we optimized novel monobactams for stability against SBLs, which led to the identification of LYS228 (compound 31). LYS228 is potent in the presence of all classes of β-lactamases and shows potent activity against carbapenem-resistant isolates of Enterobacteriaceae (CRE).
金属β-内酰胺酶（MBLs），如新型德里金属β-内酰胺酶（NDM-1）已在全球范围内传播并构成严重威胁。MBLs的表达使革兰氏阴性菌对所有类型的β-内酰胺抗生素产生耐药性，但单环β-内酰胺类抗生素除外，因为它们对MBLs具有内在稳定性。然而，现有的第一代单环β-内酰胺类药物如氨曲南对表达MBL的菌株临床效用有限，因为它们会受到丝氨酸β-内酰胺酶（SBLs）的影响，而SBLs在临床分离株中常常共表达。在此，我们优化了新型单环β-内酰胺类药物以提高对SBLs的稳定性，从而鉴定出LYS228（化合物31）。LYS228在所有类型的β-内酰胺酶存在的情况下均具有效力，并且对碳青霉烯耐药肠杆菌科（CRE）分离株显示出强大的活性。
