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JAC Advance Access originally published online on July 15, 2005
Journal of Antimicrobial Chemotherapy 2005 56(3):513-518; doi:10.1093/jac/dki256
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© The Author 2005. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oupjournals.org

Pyrrolobenzodiazepine dimers: novel sequence-selective, DNA-interactive, cross-linking agents with activity against Gram-positive bacteria

Tsveta Hadjivassileva, David E. Thurston and Peter W. Taylor*

School of Pharmacy, 29–39 Brunswick Square, London WC1N 1AX, UK

Received 31 March 2005; returned 17 June 2005; revised 21 June 2005; accepted 23 June 2005

* Corresponding author. Tel/Fax: +44-20-7753-5867; E-mail: peter.taylor{at}ulsop.ac.uk

Objectives: Pyrrolo[2,1-c][1,4]benzodiazepine (PBD) dimers are synthetic sequence-selective interstrand DNA minor-groove cross-linking agents developed from anthramycins. We investigated the antibacterial activity of three dimers, SJG-136, DRG-16 and ELB-21, which differ in the structure of the PBD monomeric unit and the length of the linker region between the two identical PBD monomers.

Methods: MICs were determined against 38 methicillin-resistant Staphylococcus aureus (MRSA), 20 vancomycin-resistant enterococci (VRE), 12 isolates of Streptococcus pyogenes, 12 of Streptococcus agalactiae, 12 of Listeria monocytogenes and 24 Gram-negative clinical isolates. Binding to double-stranded DNA was assessed by determination of the DNA melting temperature (Tm).

Results: MIC90 values for SJG-136 were 0.5 mg/L against MRSA, VRE and L. monocytogenes, 0.06 mg/L against S. pyogenes and 0.03 mg/L against S. agalactiae; these were below the maximum tolerated dose of the drug. MIC90s for DRG-16 were 0.125, >0.5, 0.125, 0.015 and <0.008 mg/L, respectively. The most potent compound was ELB-21, with corresponding MIC90 values of 0.03, 0.06, 0.06, 0.015 and 0.015 mg/L. There was little or no variation in sensitivity amongst isolates from any one species. All Gram-negative species (Acinetobacter, Pseudomonas, Klebsiella, Proteus spp.) were not susceptible due to the barrier function of the outer membrane. PBD dimers showed bactericidal activity against MRSA and VRE and there was a significant post-antibiotic effect (1.5–3.5 h). Incubation of EMRSA-16 genomic DNA (50 µM) with 20 µM ELB-21 resulted in a large increase in Tm suggesting that PBD dimers exert their antibacterial effect by cross-linking of the two DNA strands.

Conclusions: These data indicate that this novel class of antibacterial agents warrants further investigation as potential antibiotics for the treatment of severe infections caused by Gram-positive pathogens.

Keywords: DNA cross-linking agents , pyrrolobenzodiazepine dimers , Staphylococcus aureus , vancomycin-resistant enterococci , MRSA


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M. Doyle, E.-A. Feuerbaum, K. R. Fox, J. Hinds, D. E. Thurston, and P. W. Taylor
Response of Staphylococcus aureus to subinhibitory concentrations of a sequence-selective, DNA minor groove cross-linking pyrrolobenzodiazepine dimer
J. Antimicrob. Chemother., November 1, 2009; 64(5): 949 - 959.
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