Synthesis and antibacterial evaluation against resistant Gram-negative bacteria of monobactams bearing various substituents on oxime residue.

Based on the structural characteristics of aztreonam (AZN) and its target PBP3, a series of new monobactam derivatives bearing various substituents on oxime residue were prepared and evaluated for their antibacterial activities against susceptible and resistant Gram-negative bacteria. Among them, compounds 8p and 8r displayed moderate potency with MIC values of 0.125-32 μg/mL against most tested Gram-negative strains, comparable to AZN. Meanwhile, the combination of 8p and 8r with avibactam as a β-lactamases inhibitor, in a ratio of 1:16, showed a promising synergistic effect against both ESBLs- and NDM-1-producing K. pneumoniae, with significantly reduced MIC values up to 8-fold and >256-fold respectively. Furthermore, both of them demonstrated excellent safety profiles both in vitro and in vivo. The results provided powerful information for further structural optimization of monobactam antibiotics to fight β-lactamase-producing resistant Gram-negative bacteria. Copyright © 2019 Elsevier Inc. All rights reserved.

Citation

Zhi-Wen Li, Xi Lu, Yan-Xiang Wang, Xin-Xin Hu, Hai-Gen Fu, Li-Mei Gao, Xue-Fu You, Sheng Tang, Dan-Qing Song. Synthesis and antibacterial evaluation against resistant Gram-negative bacteria of monobactams bearing various substituents on oxime residue. Bioorganic chemistry. 2020 Jan;94:103487

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PMID: 31831161

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