Antistaphylococcal activity of DNA-interactive pyrrolobenzodiazepine (PBD) dimers and PBD-biaryl conjugates

J Antimicrob Chemother. 2012 Jul;67(7):1683-96. doi: 10.1093/jac/dks127. Epub 2012 Apr 30.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anti-Bacterial Agents / metabolism
  • Anti-Bacterial Agents / pharmacology*
  • Benzodiazepines / metabolism
  • Benzodiazepines / pharmacology*
  • Binding Sites
  • DNA Footprinting
  • DNA, Bacterial / metabolism
  • Gene Expression Profiling
  • Methicillin-Resistant Staphylococcus aureus / drug effects*
  • Microarray Analysis
  • Microbial Viability / drug effects
  • Molecular Dynamics Simulation
  • Pyrroles / metabolism
  • Pyrroles / pharmacology*

Substances

  • Anti-Bacterial Agents
  • DNA, Bacterial
  • Pyrroles
  • pyrrolo(2,1-c)(1,4)benzodiazepine
  • Benzodiazepines