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The vast majority of bacteria require iron to grow. A significant iron acquisition strategy is the production of siderophores, which are secondary microbial metabolites synthesized to sequester iron(III). Siderophore structures encompass a variety of forms, of which highly modified peptidic siderophores are of interest herein. State‐of‐the‐art genome mining tools, such as antiSMASH (antibiotics & Secondary Metabolite Analysis SHell), hold the potential to predict and discover new peptidic siderophores, including a combinatoric suite of triscatechol siderophores framed on a triserine‐ester backbone of the general class, (DHB‐ l / d CAA‐ l Ser) 3 (CAA, cationic amino acid). Siderophores with l / d Arg, l / d Lys and l Orn, but not d Orn, were predicted in bacterial genomes. Fortuitously the d Orn siderophore was identified, yet its lack of prediction highlights the limitation of current genome mining tools. The full combinatoric suite of these siderophores, which form chiral iron(III) complexes, reveals stereospecific coordination chemistry encoded in microbial genomes. The chirality embedded in this suite of Fe(III)‐siderophores raises the question of whether the relevant siderophore‐mediated iron acquisition pathways are stereospecific and selective for ferric siderophore complexes of a defined configuration.
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Genomics-driven discovery of chiral triscatechol siderophores with enantiomeric Fe( iii ) coordination
Ferric complexes of triscatechol siderophores may assume one of two enantiomeric configurations at the iron site. Chirality is known to be important in the iron uptake process, however an understanding of the molecular features directing stereospecific coordination remains ambiguous. Synthesis of the full suite of (DHB L/D Lys L/D Ser) 3 macrolactone diastereomers, which includes the siderophore cyclic trichrysobactin (CTC), enables the effects that the chirality of Lys and Ser residues exert on the configuration of the Fe( iii ) complex to be defined. Computationally optimized geometries indicate that the Λ/Δ configurational preferences are set by steric interactions between the Lys sidechains and the peptide backbone. The ability of each (DHB L/D Lys L/D Ser) 3 diastereomer to form a stable Fe( iii ) complex prompted a genomic search for biosynthetic gene clusters (BGCs) encoding the synthesis of these diastereomers in microbes. The genome of the plant pathogen Dickeya chrysanthemi EC16 was sequenced and the genes responsible for the biosynthesis of CTC were identified. A related but distinct BGC was identified in the genome of the opportunistic pathogen Yersinia frederiksenii ATCC 33641; isolation of the siderophore from Y. frederiksenii ATCC 33641, named frederiksenibactin (FSB), revealed the triscatechol oligoester, linear -(DHB L Lys L Ser) 3 . Circular dichroism (CD) spectroscopy establishes that Fe( iii )–CTC and Fe( iii )–FSB are formed in opposite enantiomeric configuration, consistent with the results of the ferric complexes of the cyclic (DHB L/D Lys L/D Ser) 3 diastereomers.
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- Award ID(s):
- 1710761
- PAR ID:
- 10312687
- Date Published:
- Journal Name:
- Chemical Science
- Volume:
- 12
- Issue:
- 37
- ISSN:
- 2041-6520
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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Accepted Manuscript1.0
- Journal Article:
- https://doi.org/10.1039/d1sc03541j
