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

Urška Lešnik, Tadeja Lukežič, Ajda Podgoršek, Jaka Horvat, Tomaž Polak, Martin Šala, Branko Jenko, Kirsten Harmrolfs, Alain Ocampo-Sosa, Luis Martínez-Martínez, Paul R. Herron, Štefan Fujs, Gregor Kosec, Iain S. Hunter, Rolf Müller, Hrvoje Petković

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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.

Original languageEnglish
Pages (from-to)3937-3940
Number of pages4
JournalAngewandte Chemie International Edition
Volume54
Issue number13
DOIs
Publication statusPublished - 23 Mar 2015

Keywords

  • antibiotics
  • biosynthesis
  • chelocardin
  • polyketides
  • tetracyclines

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    Lešnik, U., Lukežič, T., Podgoršek, A., Horvat, J., Polak, T., Šala, M., Jenko, B., Harmrolfs, K., Ocampo-Sosa, A., Martínez-Martínez, L., Herron, P. R., Fujs, Š., Kosec, G., Hunter, I. S., Müller, R., & 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. https://doi.org/10.1002/anie.201411028