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Response of Staphylococcus aureus to subinhibitory concentrations of a sequence-selective, DNA minor groove cross-linking pyrrolobenzodiazepine dimer

Doyle, M., Feuerbaum, E.-A., Fox, Keith R., Hinds, J., Thurston, D. E. and Taylor, P. W. (2009) Response of Staphylococcus aureus to subinhibitory concentrations of a sequence-selective, DNA minor groove cross-linking pyrrolobenzodiazepine dimer Journal of Antimicrobial Chemotherapy, 64, (5), pp. 949-959. (doi:10.1093/jac/dkp325).

Record type: Article


Objectives ELB-21 is a pyrrolo[2,1-c][1,4]benzodiazepine dimer with potent antistaphylococcal activity; it binds covalently to guanine residues on opposing strands of duplex DNA, interfering with regulatory proteins and transcription elongation in a sequence-selective manner. Transcriptional and proteomic alterations induced by exposure of Staphylococcus aureus clinical isolate EMRSA-16 to ELB-21 were determined in order to define more precisely the bactericidal mechanism of the drug.
Methods DNase I footprinting was used to identify high-affinity DNA binding sites. Microarrays and gel electrophoresis were used to assess the ELB-21-induced phenotype.
Results High-affinity interstrand binding sites in which guanine residues were separated by 4 bp, and also some intrastrand cross-linking sites of variable length were identified. Exposure of EMRSA-16 to 0.015 mg/L ELB-21 elicited a 2-fold or greater up-regulation of 168 genes in logarithmic phase and 181 genes in stationary phase; the majority of genes affected were associated with resident prophages ?Sa2 and ?Sa3, pathogenicity island SaPI4 and DNA damage repair. ELB-21 induced a marked increase in the number of viable phage particles in culture supernatants. The expression of only a limited number of genes showed a >50% reduction. Sixteen extracellular and four intracellular proteins were differentially expressed during logarithmic and stationary phases, including RecA, proteins associated with staphylococcal pathogenesis (IsaA, CspA), cell division and wall synthesis.
Conclusions ELB-21 kills S. aureus by forming multiple interstrand and intrastrand DNA cross-links, resulting in induction of the DNA damage response, derepression of resident prophages and modulation of a limited number of genes involved with cell wall synthesis.

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Published date: 10 August 2009
Organisations: Molecular and Cellular


Local EPrints ID: 206543
ISSN: 0305-7453
PURE UUID: e9d3029b-c4b4-41a9-9a24-4c88c2d17616
ORCID for Keith R. Fox: ORCID iD

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Date deposited: 22 Dec 2011 15:31
Last modified: 18 Jul 2017 10:51

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Author: M. Doyle
Author: E.-A. Feuerbaum
Author: Keith R. Fox ORCID iD
Author: J. Hinds
Author: D. E. Thurston
Author: P. W. Taylor

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