Construction of a new class of tetracycline lead structures with potent antibacterial activity through biosynthetic engineering (Biotechnical Faculty, University of Ljubljana)

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

Antimicrobial resistance and a shortage of novel antibiotics have led to an urgent need for new antibacterial drug leads.

Petković and research collaborators at the Biotechnical Faculty of the University of Ljubljana cloned the gene cluster encoding the tetracycline antibiotic chelocardin from actinobacterium Amycolatopsis sulphurea. Working with Acies Bio Ltd. (Slovenia) and by applying modern approaches to biosynthetic engineering, they have developed a new tetracycline lead structure, an amidated analogue of chelocardin, namely, 2-carboxamido-2-deacetyl-chelocardin. The new chelocardin analogue displayed significantly improved antibacterial activity.

A particularly important property of this new atypical tetracycline analogue is its activity against multidrug resistant Gram-negative pathogens, such as Pseudomonas aeruginosa, that cause complicated hospital infections in critically ill surgical patients and patients with sepsis and cystic fibrosis. The chelocardin analogue 2-carboxamido-2-deacetyl-chelocardin is currently undergoing preclinical evaluation.

Key references:

  1. Lešnik, U, Lukežič, T, Podgoršek, A, Horvat, J, Polak, T, Šala, M, Jenko, B, Harmrolfs, K, Ocampo-Sosa, A, Martínez, L, Herron, PR., Fujs, Š, Kosec, G, Hunter, IS., Müller, R, Petković, H. (2015). Construction of a new class of tetracycline lead-structure with potent antibacterial activity using biosynthetic engineering. Angew Chem Int Ed Engl. 23;54(13):3937-40.
     
  2. Petkovic, Hrvoje, Raspor, Peter, Lešnik, Urška. Genes for biosynthesis of tetracycline compounds and uses thereof : United States Patent : US 8,361,777 B2.