Synthesis and Stereochemical Determination of the Peptide Antibiotic Novo29

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 hi...

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Bibliographic Details
Published in:	Journal of organic chemistry Vol. 88; no. 4; pp. 2214 - 2220
Main Authors:	Krumberger, Maj, Li, Xingyue, Kreutzer, Adam G., Peoples, Aaron J., Nitti, Anthony G., Cunningham, Andrew M., Jones, Chelsea R., Achorn, Catherine, Ling, Losee L., Hughes, Dallas E., Nowick, James S.
Format:	Journal Article
Language:	English
Published:	United States American Chemical Society 17-02-2023
Subjects:	Amino Acids - chemistry Anti-Bacterial Agents - chemistry Anti-Bacterial Agents - pharmacology Chemistry Magnetic Resonance Spectroscopy Models, Molecular Molecular Conformation
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Summary:	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-(2R,3R)-hydroxyasparagine-OH and Fmoc-(2R,3S)-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 1H NMR spectroscopy, LC-MS, and in vitro antibiotic activity established that Novo29 contains (2R,3R)-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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 USDOE AC02-05CH11231 Figure 5 was corrected on Janaury 26, 2023.
ISSN:	0022-3263 1520-6904
DOI:	10.1021/acs.joc.2c02648