Oral Presentation The 16th Australian Peptide Conference 2025

Chemoenzymatic Synthesis of Novel Daptomycin Peptide Antibiotics (123705)

Paul Harris 1 2 , Yuhang Sui 2 , Jane R Allison 2 , Daniel Furkert 1 , Ghader Bashiri 2
  1. School of Chemical Sciences and Maurice Wilkins Centre for Molecular Biodiscovery, The University of Auckland, Auckland 1142, New Zealand
  2. School of Biological Sciences, The University of Auckland, Auckland 1142, New Zealand

Antibiotics is a crucial part of modern medicine. However, antimicrobial resistance (AMR) poses substantial global health concerns. It is estimated that 1.3 million deaths annually are related to AMR globally, projected to be 40 million deaths by 2050 if left unchecked.1 Daptomycin, approved by FDA in 2003 is used as a last resort for life-threatening infections caused by Gram-positive bacteria, with a low resistance rate (<2%). However, growing resistance has been observed in Staphylococcus aureus, Enterococcus, Enterococcus faecalis, and other Gram-positive bacteria. Commercial daptomycin is manufactured using fermentation techniques and chemoenzymatic approaches  but these methods offer limited structural modifications at specific sites.2 Total chemical synthesis of daptomycin allows for broader chemical modifications which may lead to novel antibiotics. Daptomycin contains the unusual amino acids, (S)-3-methyl-L-glutamic acid (3-MeGlu) and kynurenine (Kyn), an oxidised metabolite of the amino acid tryptophan. We3 and others4 have shown that the both 3-MeGu and Kyn are key to the biological activity. Recently it was reported N-alkylation on Kyn is tolerated and leads to a substantial increase in activity including daptomycin resistant pathogens.5,6 We will discuss our approach to functionalising the Kyn residue using a novel chemo-enzymatic approach to access modified Kyn building blocks that are then incorporated into a new total chemical synthesis of daptomycin analogues. We will also outline a simplified synthesis of the 3-MeGlu building block in enantiopure form.

(1)        Naghavi, M. et al; Global Burden of Bacterial Antimicrobial Resistance 1990–2021: The Lancet 2024, 404 (10459), 1199–1226.

(2)        Scull, E. M.; Bandari, C.; Johnson, B. P.; Gardner, E. D.; Tonelli, M.; You, J.; Cichewicz, R. H.; Singh, S. Appl. Microbiol. Biotechnol. 2020, 104 (18), 7853–7865.

(3)        Xu, B.; Hermant, Y.; Yang, S.-H.; Harris, P. W. R.; Brimble, M. A.. Chem. – Eur. J. 2019, 25 (62), 14101–14107.

(4)        Karas, J. A.; Carter, G. P.; Howden, B. P.; Turner, A. M.; Paulin, O. K. A.; Swarbrick, J. D.; Baker, Mark. A.; Li, J.; Velkov, T. J. Med. Chem. 2020, 63 (22), 13266–13290.

(5)        Guan, D.; Li, J.; Chen, F.; Li, J.; Bian, X.; Yu, Y.; Feng, X.; Lan, L.; Huang, W. A Facile and Eur. J. Med. Chem. 2023, 259, 115638.

(6)        Chow, H. Y.; Po, K. H. L.; Gao, P.; Blasco, P.; Wang, X.; Li, C.; Ye, L.; Jin, K.; Chen, K.; Chan, E. W. C.; You, X.; Yi Tsun Kao, R.; Chen, S.; Li,. J. Med. Chem. 2020, 63 (6), 3161–3171.