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<https://discovery.ucl.ac.uk/id/eprint/10104974> <http://purl.org/dc/terms/title> "A study on the antibacterial activity of pyrrolobenzodiazepine dimers"^^<http://www.w3.org/2001/XMLSchema#string> .
<https://discovery.ucl.ac.uk/id/eprint/10104974> <http://purl.org/ontology/bibo/abstract> "The pyrrolobenzodiazepines (PBDs) are a family of tricyclic antibiotics that interact within the minor groove of DNA to form monocovalent adducts. PBD dimers crosslink double-stranded DNA in a sequence selective manner and interfere with DNA transcription and translation. The aim of this study was to determine the antibacterial profile of three PBD dimers with differing sequence selectivity (SJG-136, DRG-16 & ELB-21) against clinical isolates from a range of bacterial infections and to investigate their mechanism of antibacterial action. MICs of the compounds were determined against a total of 123 clinical isolates, including methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE). MIC 90 values for the PBD dimers against Gram-positive isolates were ≤ 0.5 mg/1. All Gram-negative isolates were insensitive with MIC90 of ≥ 16 mg/1. ELB-21 was the most potent compound against all strains. Time kill kinetics of the PBD dimers against two epidemic strains of MRSA, EMRSA-15 and EMRSA-16, and a VRE isolate were determined; the PBD dimers were bactericidal within 2 hours. Addition of the PBD dimers to genomic EMRSA-16 DNA significantly increased the melting temperature of the DNA, indicating that PBD dimers efficiently cross-link bacterial DNA. ELB-21 was a more potent cross-linking agent than SJG-136. Southern blotting experiments using mecA and 16S rDNA probes provided further evidence for site- selective cross linking of the strands of the DNA duplex by subinhibitory concentrations of ELB-21 and SJG-136; these compounds blocked Eco R1 cleavage at restriction sites that encompass sites of PBD dimer cross-linking. Two-dimensional gel electrophoresis indicated that the observed cross-linking resulted in up-and down-regulation of a number of EMRSA-16 proteins. An initial evaluation of the efficacy of ELB-21 and SJG-136 in a murine peritonitis model proved inconclusive. This study demonstrates that the PBD dimers exert a bactericidal effect on Gram-positive pathogens by cross-linking strands of duplex DNA at selected sites on the bacterial genome."^^<http://www.w3.org/2001/XMLSchema#string> .
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