Development of teixobactin analogues containing hydrophobic, non-proteogenic amino acids that are highly potent against multidrug-resistant bacteria and biofilms

Article


Parmar, A., Lakshminarayanan, R., Iyer, A., Goh, E.T.L., To, T.Y., Yam, J.K.H., Yang, L., Newire, E., Robertson, M.C., Prior, S.H., Breukink, E., Madder, M. and Singh, I. 2023. Development of teixobactin analogues containing hydrophobic, non-proteogenic amino acids that are highly potent against multidrug-resistant bacteria and biofilms. European Journal of Medicinal Chemistry. 261. https://doi.org/10.1016/j.ejmech.2023.115853
TypeArticle
TitleDevelopment of teixobactin analogues containing hydrophobic, non-proteogenic amino acids that are highly potent against multidrug-resistant bacteria and biofilms
AuthorsParmar, A., Lakshminarayanan, R., Iyer, A., Goh, E.T.L., To, T.Y., Yam, J.K.H., Yang, L., Newire, E., Robertson, M.C., Prior, S.H., Breukink, E., Madder, M. and Singh, I.
Abstract

Teixobactin is a cyclic undecadepsipeptide that has shown excellent potency against multidrug-resistant pathogens, such as methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococci (VRE). In this article, we present the design, synthesis, and antibacterial evaluations of 16 different teixobactin analogues. These simplified analogues contain commercially available hydrophobic, non-proteogenic amino acid residues instead of synthetically challenging expensive L-allo-enduracididine amino acid residue at position 10 together with different combinations of arginines at positions 3, 4 and 9. The new teixobactin analogues showed potent antibacterial activity against a broad panel of Gram-positive bacteria, including MRSA and VRE strains. Our work also presents the first demonstration of the potent antibiofilm activity of teixobactin analogoues against Staphylococcus species associated with serious chronic infections. Our results suggest that the use of hydrophobic, non-proteogenic amino acids at position 10 in combination with arginine at positions 3, 4 and 9 holds the key to synthesising a new generation of highly potent teixobactin analogues to tackle resistant bacterial infections and biofilms.

KeywordsTeixobactin; Antimicrobial resistance; MRSA ; VRE; Biofilms; Antibiofilm
Sustainable Development Goals3 Good health and well-being
Middlesex University ThemeHealth & Wellbeing
PublisherElsevier
JournalEuropean Journal of Medicinal Chemistry
ISSN0223-5234
Electronic1768-3254
Publication dates
Online07 Oct 2023
PrintDec 2023
Publication process dates
Submitted09 Aug 2023
Accepted01 Oct 2023
Deposited29 Oct 2024
Output statusPublished
Accepted author manuscript
License
File Access Level
Open
Digital Object Identifier (DOI)https://doi.org/10.1016/j.ejmech.2023.115853
LanguageEnglish
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