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

Antistaphylococcal activity of DNA-interactive pyrrolobenzodiazepine (PBD) dimers and PBD-biaryl conjugates
Antistaphylococcal activity of DNA-interactive pyrrolobenzodiazepine (PBD) dimers and PBD-biaryl conjugates
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
0305-7453
1683-1696
Rahman, Khondakar M.
daf186cd-2706-4f42-9ac0-28865f0518de
Rosado, Helena
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Moreira, Joao B.
11af1ad3-6213-4af3-9562-18d85932dfff
Feuerbaum, Eva-Anne
cb7796cf-7573-4a45-aa73-a105e37b5d03
Fox, Keith R.
9da5debc-4e45-473e-ab8c-550d1104659f
Stecher, Eva
d76b546a-5dd9-4556-84dc-6c352d7a2662
Howard, Philip W.
1c34a0cd-4c24-4bf1-8ce1-a13006b57ba2
Gregson, Stephen J.
3a54e359-ae59-4e62-aa93-875c3239104c
James, Colin H.
d994899a-acbb-43d7-809e-d51d55fb90ba
de la Fuente, Maria
aa94b7e3-cc30-45d9-85df-fddccc85b2d6
Waldron, Denise E.
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Thurston, David E.
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Taylor, Peter W.
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Rahman, Khondakar M.
daf186cd-2706-4f42-9ac0-28865f0518de
Rosado, Helena
c0ceb85d-4e58-4879-af8b-74be3c49bf99
Moreira, Joao B.
11af1ad3-6213-4af3-9562-18d85932dfff
Feuerbaum, Eva-Anne
cb7796cf-7573-4a45-aa73-a105e37b5d03
Fox, Keith R.
9da5debc-4e45-473e-ab8c-550d1104659f
Stecher, Eva
d76b546a-5dd9-4556-84dc-6c352d7a2662
Howard, Philip W.
1c34a0cd-4c24-4bf1-8ce1-a13006b57ba2
Gregson, Stephen J.
3a54e359-ae59-4e62-aa93-875c3239104c
James, Colin H.
d994899a-acbb-43d7-809e-d51d55fb90ba
de la Fuente, Maria
aa94b7e3-cc30-45d9-85df-fddccc85b2d6
Waldron, Denise E.
4ea5490e-7f39-4cbc-8171-fa531a8bf1dd
Thurston, David E.
9e2a56ac-259f-4977-a087-9d97c9003fbb
Taylor, Peter W.
7457fc20-3895-4fd0-9adb-a8e721f8d7a4

Rahman, Khondakar M., Rosado, Helena, Moreira, Joao B., Feuerbaum, Eva-Anne, Fox, Keith R., Stecher, Eva, Howard, Philip W., Gregson, Stephen J., James, Colin H., de la Fuente, Maria, Waldron, Denise E., Thurston, David E. and Taylor, Peter W. (2012) Antistaphylococcal activity of DNA-interactive pyrrolobenzodiazepine (PBD) dimers and PBD-biaryl conjugates Journal of Antimicrobial Chemotherapy, 67, (7), pp. 1683-1696. (doi:10.1093/jac/dks127).

Record type: Article

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

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Published date: April 2012
Organisations: Molecular and Cellular

Identifiers

Local EPrints ID: 345238
URI: http://eprints.soton.ac.uk/id/eprint/345238
ISSN: 0305-7453
PURE UUID: 600c503c-3305-424d-9fa4-06a972ceda98
ORCID for Keith R. Fox: ORCID iD orcid.org/0000-0002-2925-7315

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Date deposited: 14 Nov 2012 13:45
Last modified: 18 Jul 2017 05:11

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Contributors

Author: Khondakar M. Rahman
Author: Helena Rosado
Author: Joao B. Moreira
Author: Eva-Anne Feuerbaum
Author: Keith R. Fox ORCID iD
Author: Eva Stecher
Author: Philip W. Howard
Author: Stephen J. Gregson
Author: Colin H. James
Author: Maria de la Fuente
Author: Denise E. Waldron
Author: David E. Thurston
Author: Peter W. Taylor

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