title: Construction of a new class of tetracycline lead structures with potent antibacterial activity through biosynthetic engineering.
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.
authors: Acies Bio, d.o.o., Tehnološki park 21, 1000 Ljubljana (Slovenia); Department of Food Science and Technology, Biotechnical Faculty, University of Ljubljana, Jamnikarjeva 101, 1000 Ljubljana (Slovenia).
authors: Urška
authors: U
authors: Lešnik
authors: Tadeja
authors: T
authors: Lukežič
authors: Ajda
authors: A
authors: Podgoršek
authors: Jaka
authors: J
authors: Horvat
authors: Tomaž
authors: T
authors: Polak
authors: Martin
authors: M
authors: Šala
authors: Branko
authors: B
authors: Jenko
authors: Kirsten
authors: K
authors: Harmrolfs
authors: Alain
authors: A
authors: Ocampo-Sosa
authors: Luis
authors: L
authors: Martínez-Martínez
authors: Paul R
authors: PR
authors: Herron
authors: Štefan
authors: Š
authors: Fujs
authors: Gregor
authors: G
authors: Kosec
authors: Iain S
authors: IS
authors: Hunter
authors: Rolf
authors: R
authors: Müller
authors: Hrvoje
authors: H
authors: Petković
mesh_terms: D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D002626:Chemistry, Pharmaceutical; D024881:Drug Resistance, Bacterial; D006090:Gram-Negative Bacteria / Q000187:drug effects; D006094:Gram-Positive Bacteria / Q000187:drug effects; D008826:Microbial Sensitivity Tests; D008968:Molecular Conformation; D015202:Protein Engineering; D013329:Structure-Activity Relationship; D013754:Tetracyclines / Q000138:chemical synthesis* / Q000494:pharmacology
chemical_list: D000900:Anti-Bacterial Agents; D013754:Tetracyclines
keywords: antibiotics; biosynthesis; chelocardin; polyketides; tetracyclines