Construction of a New Class of Tetracycline Lead Structures with Potent Antibacterial Activity through Biosynthetic Engineering

• Published in: Angewandte Chemie Vol. 127; no. 13; pp. 4009 - 4012
• Main 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
• Format: Journal Article
• Language: English; German
• Published: Weinheim WILEY-VCH Verlag 23.03.2015; WILEY‐VCH Verlag; Wiley Subscription Services, Inc
• Subjects: Antibiotics; Antibiotika; Antiinfectives and antibacterials; Biochemistry; Biosynthesen; Chelocardin; Chemistry; Drugs; Genetic engineering; Pathogens; Polyketide; Shortages; Tetracycline; Tetracyclines
• ISSN: 0044-8249; 1521-3757
• DOI: 10.1002/ange.201411028

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. Die Mischung macht's: Die Carboxamido‐Einheit ist wichtig für die biologische Aktivität der Tetracycline. Biosynthesegene (OxyD, OxyP) der Oxytetracyclin(OTC)‐Polyketid‐Synthase (PKS) aus Streptomyces rimosus wurden gezielt in Amycolatopsis sulphurea, dem Produzenten des untypischen Tetracyclins Chelocardin (CHD) exprimiert. Das entsprechende Analogon CDCHD, das mit hoher Ausbeute produziert wurde, hat eine deutlich höhere antibakterielle Aktivität.