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

Authors

  • Dr. Urška Lešnik,

    1. Acies Bio, d.o.o., Tehnološki park 21, 1000 Ljubljana (Slovenia)
    2. Department of Food Science and Technology, Biotechnical Faculty, University of Ljubljana, Jamnikarjeva 101, 1000 Ljubljana (Slovenia)
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    • These authors contributed equally to this work.

  • Dr. Tadeja Lukežič,

    1. Acies Bio, d.o.o., Tehnološki park 21, 1000 Ljubljana (Slovenia)
    2. 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)
    3. German Centre for Infection Research, Partner site Braunschweig (Germany)
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    • These authors contributed equally to this work.

  • Dr. Ajda Podgoršek,

    1. Acies Bio, d.o.o., Tehnološki park 21, 1000 Ljubljana (Slovenia)
    2. Centre of Excellence for Integrated Approaches in Chemistry and Biology of Proteins, (CIPKeBiP), Jamova 39, 1000 Ljubljana (Slovenia)
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  • Dr. Jaka Horvat,

    1. Acies Bio, d.o.o., Tehnološki park 21, 1000 Ljubljana (Slovenia)
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  • Dr. Tomaž Polak,

    1. Department of Food Science and Technology, Biotechnical Faculty, University of Ljubljana, Jamnikarjeva 101, 1000 Ljubljana (Slovenia)
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  • Dr. Martin Šala,

    1. Analytical Chemistry Laboratory, National Institute of Chemistry, Hajdrihova 19, 1001 Ljubljana (Slovenia)
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  • Branko Jenko,

    1. Acies Bio, d.o.o., Tehnološki park 21, 1000 Ljubljana (Slovenia)
    2. Centre of Excellence for Integrated Approaches in Chemistry and Biology of Proteins, (CIPKeBiP), Jamova 39, 1000 Ljubljana (Slovenia)
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  • Dr. Kirsten Harmrolfs,

    1. 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)
    2. German Centre for Infection Research, Partner site Braunschweig (Germany)
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  • Dr. Alain Ocampo-Sosa,

    1. Servicio de Microbiologia, Hospital Universario Marques de Valdecilla-IDIVAL, Avda Valdecilla s/n, 39005, Santander (Spain)
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  • Prof. Dr. Luis Martínez-Martínez,

    1. Department of Molecular Biology, School of Medicine, Institute of Biomedicine and Biotechnology, University of Cantabria, C/Albert Einstein, 22, 39011 Santander (Spain)
    2. Servicio de Microbiologia, Hospital Universario Marques de Valdecilla-IDIVAL, Avda Valdecilla s/n, 39005, Santander (Spain)
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  • Dr. Paul R. Herron,

    1. Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, 161 Cathedral Street, Glasgow, G4 0RE (UK)
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  • Dr. Štefan Fujs,

    1. Acies Bio, d.o.o., Tehnološki park 21, 1000 Ljubljana (Slovenia)
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  • Dr. Gregor Kosec,

    1. Acies Bio, d.o.o., Tehnološki park 21, 1000 Ljubljana (Slovenia)
    2. Centre of Excellence for Integrated Approaches in Chemistry and Biology of Proteins, (CIPKeBiP), Jamova 39, 1000 Ljubljana (Slovenia)
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  • Prof. Dr. Iain S. Hunter,

    1. Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, 161 Cathedral Street, Glasgow, G4 0RE (UK)
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  • Prof. Dr. Rolf Müller,

    Corresponding author
    1. 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)
    2. German Centre for Infection Research, Partner site Braunschweig (Germany)
    • Rolf Müller, 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)

      Hrvoje Petković, Acies Bio, d.o.o., Tehnološki park 21, 1000 Ljubljana (Slovenia)

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  • Prof. Dr. Hrvoje Petković

    Corresponding author
    1. Acies Bio, d.o.o., Tehnološki 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 Molecular Biology, School of Medicine, Institute of Biomedicine and Biotechnology, University of Cantabria, C/Albert Einstein, 22, 39011 Santander (Spain)
    • Rolf Müller, 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)

      Hrvoje Petković, Acies Bio, d.o.o., Tehnološki park 21, 1000 Ljubljana (Slovenia)

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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.

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