The minor groove-binding agent ELB-21 forms multiple interstrand and intrastrand covalent cross-links with duplex DNA and displays potent bactericidal activity against methicillin-resistant Staphylococcus aureus

Rosado, H., Rahman, K.M., Feuerbaum, E-A., Hinds, J., Thurston, D.E. and Taylor, P.W. (2011) The minor groove-binding agent ELB-21 forms multiple interstrand and intrastrand covalent cross-links with duplex DNA and displays potent bactericidal activity against methicillin-resistant Staphylococcus aureus. Journal of Antimicrobial Chemotherapy, 66 (5). pp. 985-996. 10.1093/jac/dkr044.

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DOI: 10.1093/jac/dkr044

Abstract

Objectives: The antistaphylococcal pyrrolobenzodiazepine dimer ELB-21 forms multiple adducts with duplex DNA through covalent interactions with appropriately spaced guanine residues; it is now known to form interstrand and intrastrand adducts with oligonucleotide sequences of variable length. We determined the DNA sequence preferences of ELB-21 in relation to its capacity to exert a bactericidal effect by damaging DNA. Methods: Formation of adducts by ELB-21 and 12- to 14-mer DNA duplexes was investigated using ion-pair reversed phase liquid chromatography and mass spectrometry. Drug-induced changes in gene expression were measured in prophage-free Staphylococcus aureus RN4220 by microarray analysis. Results: ELB-21 preferentially formed intrastrand adducts with guanines separated by three nucleotide base pairs. Interstrand and intrastrand adducts were formed with duplexes both longer and shorter than the preferred target sequences. ELB-21 elicited rapid bactericidal effects against prophage-carrying and prophage-free S. aureus strains; cell lysis occurred following activation and release of resident prophages. Killing appeared to be due to irreparable damage to bacterial DNA and susceptibility to ELB-21 was governed by the capacity of staphylococci to repair DNA lesions through induction of the SOS DNA damage response mediated by the RecA-LexA pathway. Conclusions: Thedata support the contention that ELB-21 arrestsDNAreplication, eliciting formationof ssDNA-RecA filaments that inactivate LexA, the SOS repressor, and phage repressors such as Cl, resulting in activation of the DNA damage response and de-repression of resident prophages. Above the MIC threshold, DNA repair is ineffective.

Item Type:Article
Additional Information:antistaphylococcal activity, pyrrolobenzodiazepine dimer, DNA cross-linking, DNA adduct formation, MRSA
Departments, units and centres:Department of Pharmaceutics > Department of Pharmaceutics
ID Code:2625
Journal or Publication Title:Journal of Antimicrobial Chemotherapy
Deposited By:Library Staff
Deposited On:02 Dec 2011 17:55
Last Modified:02 Dec 2011 17:55

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