DNA sequence-selective C8-linked pyrrolobenzodiazepine(PBD)-heterocyclic polyamide conjugates show anti-tubercular specific activities

Federico Brucoli, Juan D. Guzman, Mohammad A. Basher, Dimitrios Evangelopoulos, Eleanor McMahon, Tulika Munshi, Timothy D. McHugh, Keith R. Fox, Sanjib Bhakta

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New chemotherapeutic agents with novel mechanisms of action are in urgent need to combat the tuberculosis pandemic. A library of 12 C8-linked pyrrolo[2,1-c][1,4]benzodiazepine (PBD)–heterocyclic polyamide conjugates (1–12) was evaluated for anti-tubercular activity and DNA sequence selectivity. The PBD conjugates were screened against slow-growing Mycobacterium bovis Bacillus Calmette-Guérin and M. tuberculosis H37Rv, and fast-growing Escherichia coli, Pseudomonas putida and Rhodococcus sp. RHA1 bacteria. DNase I footprinting and DNA thermal denaturation experiments were used to determine the molecules’ DNA recognition properties. The PBD conjugates were highly selective for the mycobacterial strains and exhibited significant growth inhibitory activity against the pathogenic M. tuberculosis H37Rv, with compound 4 showing MIC values (MIC=0.08 mg l−1) similar to those of rifampin and isoniazid. DNase I footprinting results showed that the PBD conjugates with three heterocyclic moieties had enhanced sequence selectivity and produced larger footprints, with distinct cleavage patterns compared with the two-heterocyclic chain PBD conjugates. DNA melting experiments indicated a covalent binding of the PBD conjugates to two AT-rich DNA-duplexes containing either a central GGATCC or GTATAC sequence, and showed that the polyamide chains affect the interactions of the molecules with DNA. The PBD–C8 conjugates tested in this study have a remarkable anti-mycobacterial activity and can be further developed as DNA-targeted anti-tubercular drugs.

Original languageEnglish
Pages (from-to)843-849
Number of pages7
JournalThe Journal of Antibiotics
Early online date11 May 2016
Publication statusPublished - 31 Dec 2016


  • Drug discovery
  • DNA-minor groove binding agents
  • Pyrrolobenzodiazepines
  • Anti-tubercular agents
  • DNase I footprinting
  • Mycobacterium tuberculosis
  • HT-SPOTi


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