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Optimization of novel monobactams with activity against carbapenem-resistant Enterobacteriaceae - Identification of LYS228

Reck, Folkert and Bermingham, Alun and Blais, Johanne and Capka, Vladimir and Cariaga, Taryn and Casarez, Anthony and Colvin, Richard and Dean, Charles and Fekete, Alexander and Growcott, Ellena and Guo, Hongqiu and Gong, Wanben and Jones, Adriana and Li, Cindy and Li, Fengxia and Lin, Xiaodong and Lindvall, Mika and Lopez, Sara and Mckenney, David and Metzger Iv, Louis and Moser, Heinz and Prathapam, Ramadevi and Rasper, Dita and Rudewicz, Patrick and Sethuraman, Vijay and Shen, Xiaoyu and Shaul, Jacob and Simmons, Bob and Tashiro, Kyuto and Tang, Dazhi and Tjandra, Meiliana and Turner, Nancy and Uehara, Tsuyoshi and Vitt, Charles and Whitebread, Steven and Yifru, Aregahegn and Zang, Richard and Zhu, Qingming (2018) Optimization of novel monobactams with activity against carbapenem-resistant Enterobacteriaceae - Identification of LYS228. Bioorganic and Medicinal Chemistry Letters. ISSN 14643405

Abstract

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).

Item Type: Article
Keywords: Antibiotic CRE KPC Metallo-β-lactamases Monobactam NDM-1 PBP-3 β-Lactam β-Lactamases
Date Deposited: 01 Mar 2018 00:45
Last Modified: 25 Jan 2019 00:45
URI: https://oak.novartis.com/id/eprint/34793

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