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Angew Chem Int Ed Engl. 2014 Dec 22;53(52):14605-9. doi: 10.1002/anie.201409964. Epub 2014 Dec 15.

Cystobactamids: myxobacterial topoisomerase inhibitors exhibiting potent antibacterial activity.

Author information

1
Abteilung Mikrobielle Naturstoffe, Helmholtz Institut für Pharmazeutische Forschung Saarland, Helmholtz Zentrum für Infektionsforschung, Universität des Saarlandes, Campus C2.3, 66123 Saarbrücken (Germany); Deutsches Zentrum für Infektionsforschung (DZIF), Standort Hannover-Braunschweig (Germany).

Abstract

The development of new antibiotics faces a severe crisis inter alia owing to a lack of innovative chemical scaffolds with activities against Gram-negative and multiresistant pathogens. Herein, we report highly potent novel antibacterial compounds, the myxobacteria-derived cystobactamids 1-3, which were isolated from Cystobacter sp. and show minimum inhibitory concentrations in the low μg mL(-1) range. We describe the isolation and structure elucidation of three congeners as well as the identification and annotation of their biosynthetic gene cluster. By studying the self-resistance mechanism in the natural producer organism, the molecular targets were identified as bacterial type IIa topoisomerases. As quinolones are largely exhausted as a template for new type II topoisomerase inhibitors, the cystobactamids offer exciting alternatives to generate novel antibiotics using medicinal chemistry and biosynthetic engineering.

KEYWORDS:

NRPS; antibiotics; myxobacteria; natural products; topoisomerase inhibitors

PMID:
25510965
DOI:
10.1002/anie.201409964
[Indexed for MEDLINE]

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