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

Synthesis and antibacterial evaluation against resistant Gram-negative bacteria of monobactams bearing various substituents on oxime residue.
Bioorg Chem. 2019 Dec 02;:103487
Authors: Li ZW, Lu X, Wang YX, Hu XX, Fu HG, Gao LM, You XF, Tang S, Song DQ
Abstract
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.
PMID: 31831161 [PubMed - as supplied by publisher]

Source: Bioorganic Chemistry - December 1, 2019 Category: Chemistry Authors: Li ZW, Lu X, Wang YX, Hu XX, Fu HG, Gao LM, You XF, Tang S, Song DQ Tags: Bioorg Chem Source Type: research