Synthesis and antibacterial evaluation against resistant Gram-negative bacteria of monobactams bearing various substituents on oxime residue.
Bioorg Chem
; 94: 103487, 2020 01.
Article
em En
| MEDLINE
| ID: mdl-31831161
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 ß-lactamases inhibitor, in a ratio of 116, 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 ß-lactamase-producing resistant Gram-negative bacteria.
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Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Oximas
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Monobactamas
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Escherichia coli
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Klebsiella pneumoniae
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Antibacterianos
Idioma:
En
Ano de publicação:
2020
Tipo de documento:
Article