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Strategies for the Discovery and Development of New Antibiotics from Natural Products: Three Case Studies

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How to Overcome the Antibiotic Crisis

Part of the book series: Current Topics in Microbiology and Immunology ((CT MICROBIOLOGY,volume 398))

Abstract

Natural products continue to be a predominant source for new anti-infective agents. Research at the Helmholtz Institute for Pharmaceutical Research Saarland (HIPS) and the Helmholtz Centre for Infection Research (HZI) is dedicated to the development of new lead structures against infectious diseases and, in particular, new antibiotics against hard-to-treat and multidrug-resistant bacterial pathogens. In this chapter, we introduce some of the concepts currently being employed in the field of antibiotic discovery. In particular, we will exemplarily illustrate three approaches: (1) Current sources for novel compounds are mainly soil-dwelling bacteria. In the course of our antimicrobial discovery program, a biodiverse collection of myxobacterial strains has been established and screened for antibiotic activities. Based on this effort, one successful example is presented in this chapter: Antibacterial cystobactamids were discovered and their molecular target, the DNA gyrase, was identified soon after the analysis of myxobacterial self-resistance making use of the information found in the respective biosynthesis gene cluster. (2) Besides our focus on novel natural products, we also apply strategies to further develop either neglected drugs or widely used antibiotics for which development of resistance in the clinical setting is an issue: Antimycobacterial griselimycins were first described in the 1960s but their development and use in tuberculosis therapy was not further pursued. We show how a griselimycin derivative with improved pharmacokinetic properties and enhanced potency against Mycobacterium tuberculosis revealed and validated a novel target for antibacterial therapy, the DNA sliding clamp. (3) In a third approach, biosynthetic engineering was used to modify and optimize natural products regarding their pharmaceutical properties and their production scale: The atypical tetracycline chelocardin is a natural product scaffold that was modified to yield a more potent derivative exhibiting activity against multidrug-resistant pathogens. This was achieved by genetic engineering of the producer strain and the resulting compound is now subject to further optimization by medicinal chemistry approaches.

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Authors and Affiliations

  1. Department of Microbial Natural Products, Helmholtz Centre for Infection Research (HZI) and Pharmaceutical Biotechnology, Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), Saarland University, Campus E8 1, 66123, Saarbrücken, Germany

    Jennifer Herrmann, Tadeja Lukežič, Angela Kling, Sascha Baumann & Rolf Müller

  2. German Centre for Infection Research (DZIF), Partner Site Hannover-Braunschweig, Braunschweig, Germany

    Jennifer Herrmann, Tadeja Lukežič, Angela Kling, Sascha Baumann, Stephan Hüttel & Rolf Müller

  3. Department Microbial Drugs, Helmholtz Centre for Infection Research (HZI), Inhoffenstraße 7, 38124, Braunschweig, Germany

    Stephan Hüttel

  4. Department of Food Science and Technology, Biotechnical Faculty, University of Ljubljana, Jamnikarjeva 101, 1000, Ljubljana, Slovenia

    Hrvoje Petković

Authors
  1. Jennifer Herrmann
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  2. Tadeja Lukežič
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  3. Angela Kling
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  4. Sascha Baumann
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  5. Stephan Hüttel
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  6. Hrvoje Petković
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  7. Rolf Müller
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Correspondence to Rolf Müller .

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Editors and Affiliations

  1. Department Microbial Drugs, Helmholtz Centre for Infection Research, Braunschweig, Niedersachsen, Germany

    Marc Stadler

  2. Dept. Molecular Infection Biology, Helmholtz Centre for Infection Research, Braunschweig, Niedersachsen, Germany

    Petra Dersch

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Herrmann, J. et al. (2016). Strategies for the Discovery and Development of New Antibiotics from Natural Products: Three Case Studies. In: Stadler, M., Dersch, P. (eds) How to Overcome the Antibiotic Crisis . Current Topics in Microbiology and Immunology, vol 398. Springer, Cham. https://doi.org/10.1007/82_2016_498

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