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Construction of a New Class of Tetracycline Lead Structures with Potent Antibacterial Activity through Biosynthetic Engineering |
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| Authors: | Dr. Urška Lešnik Dr. Tadeja Lukežič Dr. Ajda Podgoršek Dr. Jaka Horvat Dr. Tomaž Polak Dr. Martin Šala Branko Jenko Dr. Kirsten Harmrolfs Dr. Alain Ocampo‐Sosa Prof. Dr. Luis Martínez‐Martínez Dr. Paul R. Herron Dr. Štefan Fujs Dr. Gregor Kosec Prof. Dr. Iain S. Hunter Prof. Dr. Rolf Müller Prof. Dr. Hrvoje Petković |
| Affiliation: | 1. Acies Bio, d.o.o., Tehnolo?ki park 21, 1000 Ljubljana (Slovenia);2. Department of Food Science and Technology, Biotechnical Faculty, University of Ljubljana, Jamnikarjeva 101, 1000 Ljubljana (Slovenia);3. Department of Microbial Natural Products, Helmholtz‐Institute for Pharmaceutical Research Saarland (HIPS), Helmholtz Centre for Infection Research (HZI) and Pharmaceutical Biotechnology, Saarland University, Campus C2 3, 66123 Saarbrücken (Germany);4. German Centre for Infection Research, Partner site Braunschweig (Germany);5. Centre of Excellence for Integrated Approaches in Chemistry and Biology of Proteins, (CIPKeBiP), Jamova 39, 1000 Ljubljana (Slovenia);6. Analytical Chemistry Laboratory, National Institute of Chemistry, Hajdrihova 19, 1001 Ljubljana (Slovenia);7. Servicio de Microbiologia, Hospital Universario Marques de Valdecilla‐IDIVAL, Avda Valdecilla s/n, 39005, Santander (Spain);8. Department of Molecular Biology, School of Medicine, Institute of Biomedicine and Biotechnology, University of Cantabria, C/Albert Einstein, 22, 39011 Santander (Spain);9. Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, 161 Cathedral Street, Glasgow, G4 0RE (UK) |
| 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. |
| Keywords: | antibiotics biosynthesis chelocardin polyketides tetracyclines |