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Cystobactamide – novel antibacterials against gram-negative pathogens

Prof. Rolf Müller, Helmholtz Centre for Infection Research GmbH; Prof. Rolf Hartmann, Helmholtz Centre for Infection Research GmbH; Prof. Andreas Kirschning, Leibniz Universität Hannover; Prof. Mark Brönstrup, Helmholtz Centre for Infection Research GmbH



Infectious diseases caused by bacterial pathogens remain a major health issue, not only restricted to developing countries. In highly industrialized countries, the effects of globalization and the emergence of bacterial resistance contribute to their epidemiologic relevance. According to the European Center for Disease Control and Prevention, pathogenic bacteria from the species Klebsiella pneumoniae and Escherichia coli that display combined resistance against 3rd generation Cephalosporins, Fluoroquinolones and Aminoglycosides are on the rise. Even Carbapenem, the last resort in such cases, may prove to be futile as Klebsiella is able to develop resistance against it as well. New and innovative approaches are needed to tackle this problem.


Provided are Cystobactamides, a group of newly discovered natural products isolated from Cystobacter spec., that show strong antibacterial activity against E. coli and other gram-negative bacteria in the submicromolar range. Results from in vitro assays indicate that Cystobactamides target the bacterial gyrase, interfering with DNA replication. Only limited cross-resistance was detected. No cytotoxic activity was recognized in standard cell culture assays. The basic structure of the Cystobactamides provides a new scaffold for the generation of innovative antibiotic drugs to combat infections with gram-negative and gram-positive pathogens. The natural compound is available in sufficient amounts for further development by an established fermentative production process which can readily be optimised for large scale production by biosynthetic engineering. In addition, chemical synthesis from building blocks is established. Altogether these favourable properties qualify the new compounds for further development.

Commercial Opportunity

Cystobactamides are offered for licensing or co-development.

Development Status

Lead optimization. Production optimization and characterization of new natural derivatives, molecular definition of the target site as well as total synthesis and biosynthetic engineering of the currently most active compound and related SAR studies are ongoing.

Patent Situation

First priority was filed in July 2013. Meanwhile three patent families have been filed based on WO2015/003816, WO2016/082934 and EP17187536.2 covering a broad structural space.

Further Reading

Cheng et l. 2017. Total Syntheses of Cystobactamids and Structural Confirmation of Cystobactamid 919-2. Angew Chem Int Ed Engl. 2017 Oct 2;56(41):12755-12759. doi: 10.1002/anie.201705387


Cystobactamide – novel antibacterials against gram-negative pathogens