E-BUGS-118 - Transcription profiling by array to assess epidemic methicillin-resistant Staphylococcus aureus 16 phenotypes induced by PBD conjugates

Status
Released on 17 April 2012, last updated on 1 May 2014
Organism
Staphylococcus aureus
Samples (2)
Array (1)
Protocols (7)
Description
Objectives Pyrrolobenzodiazepine (PBD) dimers, tethered through inert propyldioxy or pentyldioxy linkers, possess potent bactericidal activity against a range of Gram-positive bacteria by virtue of their capacity to cross-link duplex DNA in sequence-selective fashion. Here we attempt to improve the antibacterial activity and cytotoxicity profile of PBD-containing conjugates by extension of dimer linkers and replacement of one PBD unit with phenyl-substituted or benzo-fused heterocycles that facilitate non-covalent interactions with duplex DNA. Methods DNase I footprinting was used to identify high-affinity DNA binding sites. A staphylococcal gene microarray was used to assess epidemic methicillin-resistant Staphylococcus aureus 16 phenotypes induced by PBD conjugates. Molecular dynamics simulations were employed to investigate the accommodation of compounds within the DNA helix. Results Increasing the length of the linker in PBD dimers led to a progressive reduction in antibacterial activity, but not in their cytotoxic capacity. Complex patterns of DNA binding were noted for extended PBD dimers. Modelling of DNA strand cross-linking by PBD dimers indicated distortion of the helix. A majority (26 of 43) of PBD-biaryl conjugates possessed potent antibacterial activity with little or no helical distortion and a more favourable cytotoxicity profile. Bactericidal activity of PBD-biaryl conjugates was determined by inability to excise covalently bound drug molecules from bacterial duplex DNA. Conclusions PBD-biaryl conjugates have a superior antibacterial profile compared with PBD dimers such as ELB-21. We have identified six PBD-biaryl conjugates as potential drug development candidates. [Data is also available from http://bugs.sgul.ac.uk/E-BUGS-118]
Experiment types
transcription profiling by array, compound treatment
Contact
Citation
Antistaphylococcal activity of DNA-interactive pyrrolobenzodiazepine (PBD) dimers and PBD-biaryl conjugates. Rahman, Khondaker M.; Rosado, Helena; Moreira, Joao B.; Feuerbaum, Eva-Anne; Fox, Keith R.; Stecher, Eva; Howard, Philip W.; Gregson, Stephen J.; James, Colin H.; de la Fuente, Maria; Waldron, Denise E.; Thurston,David E.; Taylor, Peter W. Journal of Antimicrobial Chemotherapy 67(7):1683 (2012), Europe PMC 22547662
MIAME
PlatformsProtocolsVariablesProcessedRaw
Files
Investigation descriptionE-BUGS-118.idf.txt
Sample and data relationshipE-BUGS-118.sdrf.txt
Raw data (1)E-BUGS-118.raw.1.zip
Array designA-BUGS-17.adf.txt
R ExpressionSetE-BUGS-118.eSet.r
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