Aquimarins, Peptide Antibiotics with Amino-Modified C-Termini from a Sponge-Derived Aquimarina sp. Bacterium

Angew Chem Int Ed Engl. 2022 Feb 14;61(8):e202115802. doi: 10.1002/anie.202115802. Epub 2021 Dec 28.

Abstract

Genome mining and bioactivity studies suggested the sponge-derived bacterium Aquimarina sp. Aq135 as a producer of new antibiotics. Activity-guided isolation identified antibacterial peptides, named aquimarins, featuring a new scaffold with an unusual C-terminal amino group and chlorine moieties. Responsible for the halogenation is the FeII /α-ketoglutarate-dependent chlorinase AqmA that halogenates up to two isoleucine residues in a carrier protein-dependent fashion. Total syntheses of two natural aquimarins and eight non-natural variants were developed. Structure-activity relationship (SAR) studies with these compounds showed that the synthetically more laborious chlorinations are not required for antibacterial activity but enhance cytotoxicity. In contrast, variants lacking the C-terminal amine were virtually inactive, suggesting diamines similar to the terminal aquimarin residue as candidate building blocks for new peptidomimetic antibiotics.

Keywords: Antibiotics; Bacteria; Natural products; Nonribosomal peptides; Sponges.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anti-Bacterial Agents / chemistry*
  • Anti-Bacterial Agents / metabolism
  • Flavobacteriaceae / chemistry*
  • Molecular Conformation
  • Peptides / chemistry*
  • Peptides / genetics
  • Peptides / metabolism
  • Stereoisomerism

Substances

  • Anti-Bacterial Agents
  • Peptides