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

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.

• Authors: Anish Parmar, Rajamani Lakshminarayanan, Abhishek Iyer, Eunice Tze Leng Goh, Tsz Ying To, Joey Kuok Hoong Yam, Liang Yang, Enas Newire, Maria C Robertson, Stephen H Prior, Eefjan Breukink, Annemieke Madder, Ishwar Singh
• Journal: European journal of medicinal chemistry (Eur J Med Chem) Vol. 261 Pg. 115853 (Dec 05 2023) ISSN: 1768-3254 [Electronic] France
• PMID: 37857144 (Publication Type: Journal Article)
• Copyright: Copyright © 2023 Elsevier Masson SAS. All rights reserved.

Chemical References

• teixobactin
• Amino Acids
• Anti-Bacterial Agents

Topics

• Methicillin-Resistant Staphylococcus aureus
• Structure-Activity Relationship
• Amino Acids (pharmacology)
• Vancomycin-Resistant Enterococci
• Anti-Bacterial Agents (chemistry)
• Biofilms
• Microbial Sensitivity Tests