Construction of a new class of tetracycline lead structures with potent antibacterial activity through biosynthetic engineering

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Lešnik, Urška and Lukežič, Tadeja and Podgoršek, Ajda and Horvat, Jaka and Polak, Tomaž and Šala, Martin and Jenko, Branko and Harmrolfs, Kirsten and Ocampo-Sosa, Alain and Martínez-Martínez, Luis and Herron, Paul R. and Fujs, Štefan and Kosec, Gregor and Hunter, Iain S. and Müller, Rolf and Petković, Hrvoje (2015) Construction of a new class of tetracycline lead structures with potent antibacterial activity through biosynthetic engineering. Angewandte Chemie International Edition, 54 (13). pp. 3937-3940. ISSN 1521-3773 (https://doi.org/10.1002/anie.201411028)

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Abstract

Antimicrobial resistance and the shortage of novel antibiotics have led to an urgent need for new antibacterial drug leads. Several existing natural product scaffolds (including chelocardins) have not been developed because their suboptimal pharmacological properties could not be addressed at the time. It is demonstrated here that reviving such compounds through the application of biosynthetic engineering can deliver novel drug candidates. Through a rational approach, the carboxamido moiety of tetracyclines (an important structural feature for their bioactivity) was introduced into the chelocardins, which are atypical tetracyclines with an unknown mode of action. A broad-spectrum antibiotic lead was generated with significantly improved activity, including against all Gram-negative pathogens of the ESKAPE panel. Since the lead structure is also amenable to further chemical modification, it is a platform for further development through medicinal chemistry and genetic engineering.

ORCID iDs

Lešnik, Urška, Lukežič, Tadeja, Podgoršek, Ajda, Horvat, Jaka, Polak, Tomaž, Šala, Martin, Jenko, Branko, Harmrolfs, Kirsten, Ocampo-Sosa, Alain, Martínez-Martínez, Luis, Herron, Paul R. ORCID logoORCID: https://orcid.org/0000-0003-3431-1803, Fujs, Štefan, Kosec, Gregor, Hunter, Iain S. ORCID logoORCID: https://orcid.org/0000-0003-2571-6016, Müller, Rolf and Petković, Hrvoje;
  • Item type:Article
    ID code:53468
    Dates:
    Date
    Event
    23 March 2015
    Published
    16 December 2014
    Accepted
    Notes:This is the accepted version of the following article: Lešnik, U., Lukežič, T., Podgoršek, A., Horvat, J., Polak, T., Šala, M., ... Petković, H. (2015). Construction of a new class of tetracycline lead structures with potent antibacterial activity through biosynthetic engineering. Angewandte Chemie International Edition, 54(13), 3937-3940. which has been published in final form at http://onlinelibrary.wiley.com/doi/10.1002/anie.201411028/abstract.
    Subjects:Medicine > Pharmacy and materia medica
    Department:Faculty of Science > Strathclyde Institute of Pharmacy and Biomedical Sciences
    Depositing user: Pure Administrator
    Date deposited:24 Jun 2015 12:52
    Last modified:14 Dec 2024 01:17
    Related URLs:
    URI:https://strathprints.strath.ac.uk/id/eprint/53468
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