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

DNA sequence-selective C8-linked pyrrolobenzodiazepine-heterocyclic polyamide conjugates show anti-tubercular-specific activities
DNA sequence-selective C8-linked pyrrolobenzodiazepine-heterocyclic polyamide conjugates show anti-tubercular-specific activities
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.
0021-8820
843-849
Bucoli, Frederico
aa0c06bf-846e-4041-8f42-73b93ff88ce3
Guzman, Juan
f3f27497-9fdf-4db8-a7c9-dcd032b21cdb
Basher, Mohammad
0dc21808-a279-45b1-b73a-9860c904f178
Evangelopoulos, Dimitrios
6b430e99-8f4d-48a5-9dad-47eac937c26b
McMahon, Eleanor
ca7da016-04fb-4ce2-a0c2-884ed47f7878
Munshi, Tulika
0eb304c9-9799-47b9-9f01-24ee17564f21
McHugh, Timothy D.
68ecc8b4-8354-49c1-85c3-9f4c81b43f93
Fox, Keith
9da5debc-4e45-473e-ab8c-550d1104659f
Bhakta, Sanjib
0a43be80-fe0f-403b-b4d2-2b8e88e6c5ac
Bucoli, Frederico
aa0c06bf-846e-4041-8f42-73b93ff88ce3
Guzman, Juan
f3f27497-9fdf-4db8-a7c9-dcd032b21cdb
Basher, Mohammad
0dc21808-a279-45b1-b73a-9860c904f178
Evangelopoulos, Dimitrios
6b430e99-8f4d-48a5-9dad-47eac937c26b
McMahon, Eleanor
ca7da016-04fb-4ce2-a0c2-884ed47f7878
Munshi, Tulika
0eb304c9-9799-47b9-9f01-24ee17564f21
McHugh, Timothy D.
68ecc8b4-8354-49c1-85c3-9f4c81b43f93
Fox, Keith
9da5debc-4e45-473e-ab8c-550d1104659f
Bhakta, Sanjib
0a43be80-fe0f-403b-b4d2-2b8e88e6c5ac

Bucoli, Frederico, Guzman, Juan, Basher, Mohammad, Evangelopoulos, Dimitrios, McMahon, Eleanor, Munshi, Tulika, McHugh, Timothy D., Fox, Keith and Bhakta, Sanjib (2016) DNA sequence-selective C8-linked pyrrolobenzodiazepine-heterocyclic polyamide conjugates show anti-tubercular-specific activities. The Journal of Antibiotics, 69, 843-849. (doi:10.1038/ja.2016.43).

Record type: Article

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.

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More information

Accepted/In Press date: 16 March 2016
e-pub ahead of print date: 11 May 2016
Published date: December 2016
Organisations: Molecular and Cellular, Faculty of Natural and Environmental Sciences, Centre for Biological Sciences

Identifiers

Local EPrints ID: 405825
URI: https://eprints.soton.ac.uk/id/eprint/405825
ISSN: 0021-8820
PURE UUID: b3293d04-86bc-4f45-9b2a-ed0880081e79
ORCID for Keith Fox: ORCID iD orcid.org/0000-0002-2925-7315

Catalogue record

Date deposited: 18 Feb 2017 00:19
Last modified: 07 Aug 2019 00:54

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