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- Title
Construction of a New Class of Tetracycline Lead Structures with Potent Antibacterial Activity through Biosynthetic Engineering.
- Authors
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.; Fujs, Štefan; Kosec, Gregor; Hunter, Iain S.; Müller, Rolf; Petković, Hrvoje
- 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.
- Subjects
TETRACYCLINE; ANTIBACTERIAL agents; BIOSYNTHESIS; GENETIC engineering; PHARMACEUTICAL chemistry; ANTIBIOTICS
- Publication
Angewandte Chemie International Edition, 2015, Vol 54, Issue 13, p3937
- ISSN
1433-7851
- Publication type
Article
- DOI
10.1002/anie.201411028