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

Singh, Ishwar and Malkawi, Ruba and Iyer, Abhishek and Parmar, Anish and Lloyd, Daniel and Goh, E and Taylor, Edward and Sarmad, Sarir and Madder, A and Lakshminarayanan, R (2018) Cysteines and Disulfide-Bridged Macrocyclic Mimics of Teixobactin Analogues and Their Antibacterial Activity Evaluation against Methicillin-Resistant Staphylococcus Aureus (MRSA). Pharmaceutics, 10 (4). p. 183. ISSN 1999-4923

Full content URL: https://doi.org/10.3390/pharmaceutics10040183

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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.

Additional Information:This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).
Keywords:Teixobactins, antibiotics, antimicrobials, peptide synthesis
Subjects:F Physical Sciences > F150 Medicinal Chemistry
C Biological Sciences > C500 Microbiology
C Biological Sciences > C720 Biological Chemistry
Divisions:College of Science > School of Pharmacy
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ID Code:33705
Deposited On:17 Oct 2018 09:09

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