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    Activity of DNA-targeted C8-linked pyrrolobenzodiazepine(PBD)-heterocyclic polyamide conjugates against aerobically and hypoxically grown Mycobacterium tuberculosis under acidic and neutral conditions

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    Brucoli article proofs_41429_2018_68_Author.pdf (547.4Kb)
    JA-23239 Amended manuscript_PBDs - dormant M tb_Brucoli 24-04-18.docx (51.29Kb)
    Date
    2018-05-24
    Author
    Iacobino, Angelo;
    Giannoni, Federico;
    Fattorini, Lanfranco;
    Brucoli, F.
    Metadata
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    Abstract
    Mycobacterium tuberculosis (Mtb) is the aetiological agent of tuberculosis, the leading cause of death worldwide from a single infectious agent. Mtb is a highly-adaptable human pathogen that might enter a dormant non-replicating (NR), drug-tolerant stage. Reactivation of dormant Mtb can lead to active disease. Antibiotic treatments of active and latent tuberculosis are long, complex and may fail to fully eradicate the infection. Therefore, it is imperative to identify novel compounds with new mechanism of actions active against NR-bacilli. Dormant Mtb habitat is mostly thought to be the pH-neutral and hypoxic caseous granuloma. We have used the Wayne culture model to reproduce this environment and tested the activities of two DNA-targeted agents, C8-linked-pyrrolobenzodiazepine(PBD)-polyamide-conjugates 1 and 2, against Mtb grown in aerobic and hypoxic conditions in both acidic and pH-neutral media. PBD 2 showed growth inhibitory activity at 5.1 µg/ml against 19-day old hypoxic NR Mtb cultures with 1.8 log10-CFU reduction on day 21 at pH 7.3. PBD 2 was particularly effective against 5-day old aerobic cells at pH 7.3, with CFU reduction (6.8 log10) on day 21 at 5.1 µg/ml being identical to that of rifampin at 8 µg/ml. PBD 2 qualifies as a promising lead against aerobic and NR Mtb.
    Description
    The file attached to this record is the author's final peer reviewed version. The Publisher's final version can be found by following the DOI link.
    Citation : Iacobino, A., Giannoni, F., Fattorini, L. and Brucoli, F. (2018) Activity of DNA-targeted C8-linked pyrrolobenzodiazepine–heterocyclic polyamide conjugates against aerobically and hypoxically grown Mycobacterium tuberculosis under acidic and neutral conditions. The Journal of Antibiotics, 71, pp. 831-834
    URI
    http://hdl.handle.net/2086/16424
    DOI
    https://dx.doi.org/10.1038/s41429-018-0068-5
    Research Institute : Leicester Institute for Pharmaceutical Innovation - From Molecules to Practice (LIPI)
    Peer Reviewed : Yes
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    • Leicester School of Pharmacy [1194]

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