Interactions of pyrrolobenzodiazepine dimers and duplex DNA from methicillin-resistant Staphylococcus aureus.
Binding of two bactericidal pyrrolobenzodiazepine (PBD) dimers, SJG-136 and ELB-21, to genomic DNA from Staphylococcus aureus EMRSA-16 was investigated. Both agents cross-linked purified EMRSA-16 DNA. The more potent agent, ELB-21, had a greater capacity to cross-link DNA after incubation with intact cells than SJG-136. Extensive interstrand cross-linking at multiple sites on the EMRSA-16 genome was demonstrated by probing EcoRI-restricted DNA with mecA and 16S rDNA. Cross-linking was again greater in DNA extracted from ELB-21-treated cells and was compatible with frequency analysis of preferred binding sequences in EMRSA-16 DNA. These studies support the premise that the potency of ELB-21 is due to efficient cell penetration and provide evidence that the antibacterial activity of PBD dimers results from cross-linking at specific genomic sites.
Hadjivassileva
Tsveta
T
School of Pharmacy, 29-39 Brunswick Square, London WC1N 1AX, UK.
Stapleton
Paul D
PD
Thurston
David E
DE
Taylor
Peter W
PW
D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000494:pharmacology*; D001569:Benzodiazepines / Q000737:chemistry / Q000378:metabolism*; D003432:Cross-Linking Reagents / Q000737:chemistry / Q000378:metabolism*; D004269:DNA, Bacterial / Q000737:chemistry / Q000378:metabolism*; D019281:Dimerization; D016106:Methicillin Resistance; D015394:Molecular Structure; D011758:Pyrroles / Q000737:chemistry / Q000378:metabolism*; D013211:Staphylococcus aureus / Q000187:drug effects*
D000900:Anti-Bacterial Agents; D003432:Cross-Linking Reagents; D004269:DNA, Bacterial; D011758:Pyrroles; C438462:pyrrolo(2,1-c)(1,4)benzodiazepine; D001569:Benzodiazepines