DNA sequence-selective C8-linked pyrrolobenzodiazepine–heterocyclic polyamide conjugates show anti-tubercular-specific activities

Brucoli, F. and Guzman, Juan David and Basher, M.A. and Evangelopoulos, Dimitrios and Mcmahon, Eleanor and Munshi, Tulika and McHugh, T.D. and Fox, K.R. and Bhakta, Sanjib (2016) DNA sequence-selective C8-linked pyrrolobenzodiazepine–heterocyclic polyamide conjugates show anti-tubercular-specific activities. The Journal of Antibiotics 69 , pp. 843-849. ISSN 0021-8820.

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Official URL: http://doi.org/10.1038/ja.2016.43

Abstract

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.

Metadata

Item Type:	Article
School:	Birkbeck Faculties and Schools > Faculty of Science > School of Natural Sciences
Research Centres and Institutes:	Structural Molecular Biology, Institute of (ISMB)
Depositing User:	Administrator
Date Deposited:	18 May 2016 13:46
Last Modified:	02 Aug 2023 17:23
URI:	https://eprints.bbk.ac.uk/id/eprint/15219

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