Poster Presentation International Peptide Symposium 2023

Synthesis and Biological Evaluations of Teixobactin Analogues against Gram-positive Bacteria and Biofilms (#371)

Tsz Ying Teresa To 1 2 , Anish Parmar 1 2 , Maria Robertson 1 , Rasmita Raval 3 , William Hope 1 , Ishwar Singh 1 2
  1. Antimicrobial Pharmacodynamics and Therapeutics, Department of Pharmacology and Therapeutics, Institute of Systems, Molecular & Integrative Biology, University of Liverpool, Merseyside, L7 8TX, United Kingdom
  2. Antimicrobial Drug Discovery, Department of Chemistry, School of Physical Sciences, University of Liverpool, Crown Street, Liverpool, L69 7ZD, Merseyside, United Kingdom
  3. Surface Science Research Centre, Department of Chemistry, School of Physical Sciences, University of Liverpool, Liverpool, L69 3BX, Merseyside, United Kingdom

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Antimicrobial resistance (AMR) represents a threat to global health, leading to an increase in mortality and morbidity rate. The ability for Gram-positive bacteria to form communities on surfaces as biofilms also lead to increased resistance and such infections are more difficult to treat with currently approved antibiotics. Therefore, new potent antibiotics are in need to enter the drug pipeline.

Antimicrobial peptides are a class of antimicrobials which are generated by many organisms as part of immune responses, which provide new natural products for synthetic chemists to synthesise novel antimicrobials.

Teixobactin is a macrocyclic depsipeptide presenting excellent activity against Gram-positive bacteria without detectable resistance, targeting lipid II and III to inhibit bacterial cell wall biosynthesis. Teixobactin consists of 11 amino acids with a linear chain and macrocyclic ring, which is constituted by several proteinogenic and one non-proteinogenic amino acid (ʟ-allo-enduracididine). Previous studies revealed that some residues within teixobactin can be modified to different functional groups with enhanced or no loss of antimicrobial activity. The mode of action of teixobactin analogues was analysed.

The aims of current projects are to synthesise teixobactin analogues with novel modifications and evaluate their bioactive activities against planktonic bacteria and bacterial biofilms. A broader scope of structural activity relationship for these analogues can be analysed to enhance antimicrobial activity. Libraries of teixobactin analogues were synthesised and screened by minimal inhibitory concentration (MIC) studies against Gram-positive bacteria as such as Staphylococcus aureus. Potent teixobactin analogues were further studied to analyse the antibiofilm properties against bacterial biofilms. Biological data can provide information on the lead drug candidates for further in vitro and in vivo studies against Gram-positive bacteria and associated biofilms.

  1. Ling, L. L.; Schneider, T.; Peoples, A. J.; Spoering, A. L.; Engels, I.; Conlon, B. P.; Mueller, A.; Schäberle, T. F.; Hughes, D. E.; Epstein, S.; Jones, M.; Lazarides, L.; Steadman, V. A.; Cohen, D. R.; Felix, C. R.; Fetterman, K. A.; Millett, W. P.; Nitti, A. G.; Zullo, A. M.; Chen, C.; Lewis, K. A New Antibiotic Kills Pathogens without Detectable Resistance. Nature 2015, 517 (7535), 455–459. https://doi.org/10.1038/nature14098.
  2. Parmar, A.; Iyer, A.; Vincent, C. S.; Van Lysebetten, D.; Prior, S. H.; Madder, A.; Taylor, E. J.; Singh, I. Efficient Total Syntheses and Biological Activities of Two Teixobactin Analogues. Chem. Commun. 2016, 52 (36), 6060–6063. https://doi.org/10.1039/C5CC10249A.
  3. Parmar, A.; Iyer, A.; Prior, S. H.; Lloyd, D. G.; Leng Goh, E. T.; Vincent, C. S.; Palmai-Pallag, T.; Bachrati, C. Z.; Breukink, E.; Madder, A.; Lakshminarayanan, R.; Taylor, E. J.; Singh, I. Teixobactin Analogues Reveal Enduracididine to Be Non-Essential for Highly Potent Antibacterial Activity and Lipid II Binding. Chem. Sci. 2017, 8 (12), 8183–8192. https://doi.org/10.1039/C7SC03241B.
  4. Parmar, A.; Prior, S. H.; Iyer, A.; Vincent, C. S.; Van Lysebetten, D.; Breukink, E.; Madder, A.; Taylor, E. J.; Singh, I. Defining the Molecular Structure of Teixobactin Analogues and Understanding Their Role in Antibacterial Activities. Chem. Commun. 2017, 53 (12), 2016–2019. https://doi.org/10.1039/C6CC09490B.
  5. Parmar, A.; Iyer, A.; Lloyd, D. G.; Vincent, C. S.; Prior, S. H.; Madder, A.; Taylor, E. J.; Singh, I. Syntheses of Potent Teixobactin Analogues against Methicillin-Resistant Staphylococcus Aureus (MRSA) through the Replacement of l-Allo-Enduracididine with Its Isosteres. Chem. Commun. 2017, 53 (55), 7788–7791. https://doi.org/10.1039/C7CC04021K.
  6. Parmar, A.; Lakshminarayanan, R.; Iyer, A.; Mayandi, V.; Leng Goh, E. T.; Lloyd, D. G.; Chalasani, M. L. S.; Verma, N. K.; Prior, S. H.; Beuerman, R. W.; Madder, A.; Taylor, E. J.; Singh, I. Design and Syntheses of Highly Potent Teixobactin Analogues against Staphylococcus Aureus, Methicillin-Resistant Staphylococcus Aureus (MRSA), and Vancomycin-Resistant Enterococci (VRE) in Vitro and in Vivo. J. Med. Chem. 2018, 61 (5), 2009–2017. https://doi.org/10.1021/acs.jmedchem.7b01634.
  7. Shukla, R.; Medeiros-Silva, J.; Parmar, A.; Vermeulen, B. J. A.; Das, S.; Paioni, A. L.; Jekhmane, S.; Lorent, J.; Bonvin, A. M. J. J.; Baldus, M.; Lelli, M.; Veldhuizen, E. J. A.; Breukink, E.; Singh, I.; Weingarth, M. Mode of Action of Teixobactins in Cellular Membranes. Nat. Commun. 2020, 11 (1), 2848. https://doi.org/10.1038/s41467-020-16600-2.