| Literature DB >> 29336873 |
Folkert Reck1, Alun Bermingham2, Johanne Blais2, Vladimir Capka3, Taryn Cariaga4, Anthony Casarez2, Richard Colvin3, Charles R Dean2, Alex Fekete3, Wanben Gong5, Ellie Growcott2, Hongqiu Guo3, Adriana K Jones2, Cindy Li2, Fengxia Li2, Xiaodong Lin2, Mika Lindvall2, Sara Lopez2, David McKenney6, Louis Metzger2, Heinz E Moser2, Ramadevi Prathapam2, Dita Rasper2, Patrick Rudewicz2, Vijay Sethuraman2, Xiaoyu Shen2, Jacob Shaul2, Robert L Simmons2, Kyuto Tashiro2, Dazhi Tang2, Meiliana Tjandra7, Nancy Turner2, Tsuyoshi Uehara2, Charles Vitt2, Steven Whitebread3, Aregahegn Yifru2, Xu Zang8, Qingming Zhu2.
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).Entities:
Keywords: Antibiotic; CRE; KPC; Metallo-β-lactamases; Monobactam; NDM-1; PBP-3; β-Lactam; β-Lactamases
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Year: 2018 PMID： 29336873 DOI： 10.1016/j.bmcl.2018.01.006
Source DB: PubMed Journal: Bioorg Med Chem Lett ISSN： 0960-894X Impact factor: 2.823