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

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 1433-7851

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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.