Summary of Study ST001995

This data is available at the NIH Common Fund's National Metabolomics Data Repository (NMDR) website, the Metabolomics Workbench, https://www.metabolomicsworkbench.org, where it has been assigned Project ID PR001267. The data can be accessed directly via it's Project DOI: 10.21228/M8XX3Q This work is supported by NIH grant, U2C- DK119886.

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This study contains a large results data set and is not available in the mwTab file. It is only available for download via FTP as data file(s) here.

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Study IDST001995
Study TitleMutasynthetic production and antimicrobial characterisation of Darobactin darobactin analogs (MS analysis)
Study SummaryThere is great need for therapeutics against multi-drug resistant, Gram-negative bacterial pathogens. Recently, darobactin A, a novel bicyclic heptapeptide that selectively kills Gram-negative bacteria by targeting the outer-membrane protein BamA, was discovered. Its efficacy was proven in animal infection models of Escherichia coli, Klebsiella pneumoniae and Pseudomonas aeruginosa, thus promoting darobactin A as a promising lead compound. Originally discovered from members of the nematode symbiotic genus Photorhabdus, the biosynthetic gene cluster (BGC) encoding for the synthesis of darobactin A can also be found in other γ-proteobacterial families. Therein, the precursor peptides DarB-F, which differ in their core sequence from darobactin A, were identified in silico. Even though production of these analogs was not observed in the putative producer strains, we were able to generate them by mutasynthetic derivatization of a heterologous expression system. The generated analogs were isolated and tested for their bioactivity. The most potent compound, darobactin B, was used for co-crystallization with the target BamA, revealing an identical binding site to darobactin A. Besides its potency, darobactin B did not exhibit cytotoxicity and was slightly more active against Acinetobacter baumanii isolates than darobactin A. Furthermore, we evaluated the plasma protein binding of darobactin A and B, indicating their different pharmacokinetic properties. This is the first report on new members of this new antibiotics class, which is likely to expand to several promising therapeutic candidates.
Institute
Justus-Liebig-University Giessen
LaboratorySchäberle Laboratory
Last NameMettal
First NameUte
AddressOhlebergsweg 12, Gießen, Hesse, 35392, Germany
EmailUte.Mettal@chemie.uni-giessen.de
Phone+49 641 97219 142
Submit Date2021-11-18
Raw Data AvailableYes
Raw Data File Type(s)mzXML, d
Analysis Type DetailLC-MS
Release Date2022-11-21
Release Version1
Ute Mettal Ute Mettal
https://dx.doi.org/10.21228/M8XX3Q
ftp://www.metabolomicsworkbench.org/Studies/ application/zip

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Factors:

Subject type: Bacteria; Subject species: Escherichia coli (Factor headings shown in green)

mb_sample_id local_sample_id Forward Primer Reverse Primer
SA186768SA184025CCTAAGATCCCTGAGATCACGGCCTGGAACTGGACAAAAAGATTC TTTAGAATCTTTTTGTCCAGTTCCAGGCCGTGATCTCAGGGATCT
SA186769SA184024CCTAAGATCCCTGAGATCACGGCCTGGAACTGGTCAAAAAGCTTC TTTAGAAGCTTTTTGACCAGTTCCAGGCCGTGATCTCAGGGATCT
SA186770SA184027CCTAAGATCCCTGAGATCACGGCCTGGAACTGGTCAAGAAGCTTC TTTAGAAGCTTCTTGACCAGTTCCAGGCCGTGATCTCAGGGATCT
SA186771SA184029CCTAAGATCCCTGAGATCACGGCCTGGAAGTGGTCAAAGAATCTT TTTAAAGATTCTTTGACCACTTCCAGGCCGTGATCTCAGGGATCT
SA186772SA184028CCTAAGATCCCTGAGATCACGGCCTGGTCATGGTCAAAGAGCTTC TTTAGAAGCTCTTTGACCATGACCAGGCCGTGATCTCAGGGATCT
SA186773SA184026CCTAAGATCCCTGAGATCACGGCCTGGTCATGGTCAAGATCATTC TTTAGAATGATCTTGACCATGACCAGGCCGTGATCTCAGGGATCT
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