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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dc.cclicenceCC-BY-NCen
dc.contributor.authorIacobino, Angeloen
dc.contributor.authorGiannoni, Federicoen
dc.contributor.authorFattorini, Lanfrancoen
dc.contributor.authorBrucoli, Federicoen
dc.date.acceptance2018-04-26en
dc.date.accessioned2018-08-02T10:52:14Z
dc.date.available2018-08-02T10:52:14Z
dc.date.issued2018-05-24
dc.descriptionThe 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.en
dc.description.abstractMycobacterium 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.en
dc.funderItalian Ministry of Healthen
dc.identifier.citationIacobino, 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. 831-834en
dc.identifier.doihttps://doi.org/10.1038/s41429-018-0068-5
dc.identifier.urihttp://hdl.handle.net/2086/16424
dc.language.isoenen
dc.peerreviewedYesen
dc.projectidCCM Projecten
dc.publisherSpringer Natureen
dc.researchinstituteLeicester Institute for Pharmaceutical Innovation - From Molecules to Practice (LIPI)en
dc.subjectCaseumen
dc.subjectDNA-sequence selectiveen
dc.subjectdormancyen
dc.subjectMycobacterium tuberculosisen
dc.subjectpyrrolobenzodiazepinesen
dc.subjecttuberculosisen
dc.titleActivity of DNA-targeted C8-linked pyrrolobenzodiazepine(PBD)-heterocyclic polyamide conjugates against aerobically and hypoxically grown Mycobacterium tuberculosis under acidic and neutral conditionsen
dc.typeArticleen

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