Optimization of novel monobactams with activity against carbapenem-resistant Enterobacteriaceae - Identification of LYS228.
2018
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
monobactamdrugs like
aztreonamhave 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
monobactamsfor 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).
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