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.