Picconi, P.; Hind, C.K.; Sutton, J.M.; Rahman, K.M. Covalent DNA Binding Is Essential for Gram-Negative Antibacterial Activity of Broad Spectrum Pyrrolobenzodiazepines. Antibiotics2022, 11, 1770.
Picconi, P.; Hind, C.K.; Sutton, J.M.; Rahman, K.M. Covalent DNA Binding Is Essential for Gram-Negative Antibacterial Activity of Broad Spectrum Pyrrolobenzodiazepines. Antibiotics 2022, 11, 1770.
Picconi, P.; Hind, C.K.; Sutton, J.M.; Rahman, K.M. Covalent DNA Binding Is Essential for Gram-Negative Antibacterial Activity of Broad Spectrum Pyrrolobenzodiazepines. Antibiotics2022, 11, 1770.
Picconi, P.; Hind, C.K.; Sutton, J.M.; Rahman, K.M. Covalent DNA Binding Is Essential for Gram-Negative Antibacterial Activity of Broad Spectrum Pyrrolobenzodiazepines. Antibiotics 2022, 11, 1770.
Abstract
It is urgent to find new antibiotic classes to replenish the empty development pipeline of antibiotics. Recently, pyrrolobenzodiazepines (PBDs) with a C8-linked aliphatic-heterocycle have been identified as a new broad spectrum antibiotic class with activity against Gram-negative bacteria. The active imine moiety of the reported lead pyrrolobenzodiazepine compounds was replaced with amide to obtain the non-DNA binding and non-cytotoxic dilactam analogues to further understand the structure activity relationship and improve the safety potential of this class. The synthesized compounds were tested against panels of multidrug resistant Gram-positive and Gram-negative bacteria, including WHO priority pathogens. Minimum inhibitory concentrations for the dilactam analogues ranged from 4 – 32 mg/L for MDR Gram-positive bacteria, compared to 0.03 to 2 mg/L for the corresponding imine analogues while they were found to be inactive against MDR Gram-negative bacteria, with an MIC >32 mg/L, compared to an MIC of 0.5 to 32 mg/L. A molecular modelling study suggests the lack of imine functionality also affects the interaction of PBDs with DNA gyrase. This study suggests the presence of N10-C11 imine moiety is crucial for broad spectrum activity of pyrrolobenzodiazepines.
Keywords
antimicrobial resistance; broad-spectrum antibiotics; antibacterial drug discovery; gram-negative bacteria; pyrrolobenzodiazepines
Subject
Chemistry and Materials Science, Medicinal Chemistry
Copyright:
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