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Synthesis and Stereochemical Determination of the Peptide Antibiotic Novo29.

Maj KrumbergerXingyue LiAdam G KreutzerAaron J PeoplesAnthony G NittiAndrew M CunninghamChelsea R JonesCatherine AchornLosee L LingDallas E HughesJames S Nowick
Published in: The Journal of organic chemistry (2023)
This paper describes the synthesis and stereochemical determination of Novo29 (clovibactin), a new peptide antibiotic that is related to teixobactin and is active against Gram-positive bacteria. Novo29 is an eight-residue depsipeptide that contains the noncanonical amino acid hydroxyasparagine of hitherto undetermined stereochemistry in a macrolactone ring. The amino acid building blocks Fmoc-(2 R ,3 R )-hydroxyasparagine-OH and Fmoc-(2 R ,3 S )-hydroxyasparagine-OH were synthesized from ( R , R )- and ( S , S )-diethyl tartrate. Novo29 and epi -Novo29 were then prepared by solid-phase peptide synthesis using these building blocks. Correlation with an authentic sample of Novo29 through 1 H NMR spectroscopy, LC-MS, and in vitro antibiotic activity established that Novo29 contains (2 R ,3 R )-hydroxyasparagine. X-ray crystallography reveals that epi -Novo29 adopts an amphiphilic conformation, with a hydrophobic surface and a hydrophilic surface. Four sets of epi -Novo29 molecules pack in the crystal lattice to form a hydrophobic core. The macrolactone ring adopts a conformation in which the main-chain amide NH groups converge to create a cavity, which binds ordered water and acetate anion. The amphiphilic conformation of epi -Novo29 is reminiscent of the amphiphilic conformation adopted by the related antibiotic teixobactin and its derivatives, which contains a hydrophobic surface that interacts with the lipids of the bacterial cell membrane and a hydrophilic surface that interacts with the aqueous environment. Molecular modeling suggests that Novo29 can adopt an amphiphilic conformation similar to teixobactin, suggesting that Novo29 may interact with bacteria in a similar fashion to teixobactin.
Keyphrases
  • amino acid
  • molecular dynamics simulations
  • ionic liquid
  • magnetic resonance imaging
  • computed tomography
  • multidrug resistant
  • crystal structure
  • gram negative
  • molecularly imprinted
  • contrast enhanced