Cysteines and Disulfide-Bridged Macrocyclic Mimics of Teixobactin Analogues and Their Antibacterial Activity Evaluation against Methicillin-Resistant Staphylococcus Aureus (MRSA)

Malkawi, Ruba; Iyer, Abhishek; Parmar, Anish; Lloyd, Daniel G.; Lloyd, Daniel; Leng Goh, Eunice Tze; Leng Goh, Eunice; Taylor, Edward J.; Taylor, Edward; Sarmad, Sarir; Madder, Annemieke; Lakshminarayanan, Rajamani; Singh, Ishwar

Abstract

Teixobactin is a highly potent cyclic depsipeptide which kills a broad range of multi-drug resistant, Gram-positive bacteria, such as Methicillin-resistant Staphylococcus aureus (MRSA) without detectable resistance. In this work, we describe the design and rapid synthesis of novel teixobactin analogues containing two cysteine moieties, and the corresponding disulfide-bridged cyclic analogues. These analogues differ from previously reported analogues, such as an Arg10-teixobactin, in terms of their macrocyclic ring size, and feature a disulfide bridge instead of an ester linkage. The new teixobactin analogues were screened against Methicillin-resistant Staphylococcus aureus and Methicillin-sensitive Staphylococcus aureus. Interestingly, one teixobactin analogue containing all L-amino acid building blocks showed antibacterial activity against MRSA for the first time. Our data indicates that macrocyclisation of teixobactin analogues with disulfide bridging is important for improved antibacterial activity. In our work, we have demonstrated the unprecedented use of a disulfide bridge in constructing the macrocyclic ring of teixobactin analogues.

Citation

Malkawi, R., Iyer, A., Parmar, A., Lloyd, D. G., Lloyd, D., Leng Goh, E. T., Leng Goh, E., Taylor, E. J., Taylor, E., Sarmad, S., Madder, A., Lakshminarayanan, R., & Singh, I. (2018). Cysteines and Disulfide-Bridged Macrocyclic Mimics of Teixobactin Analogues and Their Antibacterial Activity Evaluation against Methicillin-Resistant Staphylococcus Aureus (MRSA). Pharmaceutics, 10(4), Article 183. https://doi.org/10.3390/pharmaceutics10040183

• Journal Article Type: Article
• Acceptance Date: Oct 9, 2018
• Online Publication Date: Oct 11, 2018
• Publication Date: Oct 11, 2018
• Deposit Date: Nov 3, 2023
• Publicly Available Date: Nov 28, 2023
• Journal: Pharmaceutics
• Electronic ISSN: 1999-4923
• Publisher: MDPI
• Peer Reviewed: Peer Reviewed
• Volume: 10
• Issue: 4
• Article Number: 183
• DOI: https://doi.org/10.3390/pharmaceutics10040183
• Keywords: Pharmaceutical Science
• Public URL: https://nottingham-repository.worktribe.com/output/26809628
• Publisher URL: https://www.mdpi.com/1999-4923/10/4/183
• Additional Information: © 2018 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).