Cysteines and Disulfide-Bridged Macrocyclic Mimics of Teixobactin Analogues and Their Antibacterial Activity Evaluation against Methicillin-Resistant Staphylococcus Aureus (MRSA)
Ruba Malkawi,
Abhishek Iyer,
Anish Parmar,
Daniel G. Lloyd,
Eunice Tze Leng Goh,
Edward J. Taylor,
Sarir Sarmad,
Annemieke Madder,
Rajamani Lakshminarayanan,
Ishwar Singh
Affiliations
Ruba Malkawi
School of Pharmacy, Joseph Banks Laboratories, University of Lincoln, Green Lane, Lincoln LN6 7DL, UK
Abhishek Iyer
School of Pharmacy, Joseph Banks Laboratories, University of Lincoln, Green Lane, Lincoln LN6 7DL, UK
Anish Parmar
School of Pharmacy, Joseph Banks Laboratories, University of Lincoln, Green Lane, Lincoln LN6 7DL, UK
Daniel G. Lloyd
School of Life Sciences, Joseph Banks Laboratories, University of Lincoln, Green Lane, Lincoln LN6 7DL, UK
Eunice Tze Leng Goh
Singapore Eye Research Institute, The Academia, Discovery Tower Level 6, 20 College Road, Singapore 169857, Singapore
Edward J. Taylor
School of Life Sciences, Joseph Banks Laboratories, University of Lincoln, Green Lane, Lincoln LN6 7DL, UK
Sarir Sarmad
School of Chemistry, Joseph Banks Laboratories, University of Lincoln, Green Lane, Lincoln LN6 7DL, UK
Annemieke Madder
Organic and Biomimetic Chemistry Research Group, Department of Organic and Macromolecular Chemistry, Ghent University, Krijgslaan 281 (S4), B-9000 Ghent, Belgium
Rajamani Lakshminarayanan
Singapore Eye Research Institute, The Academia, Discovery Tower Level 6, 20 College Road, Singapore 169857, Singapore
Ishwar Singh
School of Pharmacy, Joseph Banks Laboratories, University of Lincoln, Green Lane, Lincoln LN6 7DL, UK
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.
