Oral Presentation 5th Modern Solid Phase Peptide Synthesis Symposium 2015

Rationally designed fluorescent probes of the antimicrobial cyclic-lipopeptide, polymyxin B (#4)

Kade D Roberts 1 2 , Bo Yun 2 , Mohammad A K Azad 2 , Zakuan Z Deris 2 , Andrew S Horne 2 , Roger L Nation 2 , Philip E Thompson 1 2 , Tony Velkov 2 , Jian Li 2
  1. Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC, Australia
  2. Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC, Australia

Polymyxin B is a cyclic lipopeptide antibiotic that is clinically used as a last-line defense against Gram-negative ‘superbugs’. However, the effective use of this drug is hampered by its potential for nephrotoxicity.[1,2] To date, little in know about the mechanisms of activity and toxicity of the polymyxins.[3] Fluorescently labelled probes derived from a parent molecule serve as useful tools for exploring ligand/receptor interactions, membrane interactions, intracellular uptake and localisation. Previous attempts to develop fluorescent probes for polymyxins utilised semi-synthetic preparations of dansyl- or BODIPY-derived polymyxin B, where by the fluorescent group is attached to the polymyxin through non-specific acylation of the amino groups of the five Dab residues. This produces a complex mixture of mono-, di-, and tri-dansyl-substituted species that lack native antimicrobial activity and is not a good representation of the native molecule.[4]

Here we report on work to to develop improved next-generation fluorescent polymyxin probes.[5,6] To this end, we have designed and synthesized several regio-selectively modified mono-dansylated polymyxin B probes. Our design strategy was to incorporate the dansyl fluorophore into one of the two hydrophobic regions of the polymyxin B core structure. This was successfully achieved through a total synthesis approach using solid peptide synthesis incorporating orthogonal protection strategies. The chemistry utilized to prepare the probes will be presented here along with the biological evaluation of the probes.

 

  1. Velkov, T., Roberts, K. D., Nation, R. L., Thompson, P. E., Li, J. (2013), Future Microbiol. 8, 711-724.
  2. Nation, R. L., Li, J., Cars, O., Couet, W., Dudley, M. N., Kaye, K. S., Mouton, J. W., Paterson, D. L., Tam, V. H., Theuretzbacher, U., Tsuji, B. T., Turnidge, J. D. (2015), Lancet. Infect. Dis. 15, 225-234.
  3. Velkov, T., Thompson, P. E., Nation, R. L., Li, J. (2010), J. Med. Chem. 53, 1898-1916.
  4. Azad, M. A., Yun, B., Roberts, K. D., Nation, R. L., Thompson, P. E., Velkov, T., Li, J. (2014), Antimicrob. Agents. Chemother. 58, 6337-6338.
  5. Soon, R. L., Velkov, T., Chiu, F., Thompson, P. E., Kancharla, R., Roberts, K. D., Larson, I., Nation, R. L., Li, J. (2011), Anal. Biochem. 409, 273-283.
  6. Deris, Z. Z., Swarbrick, J. D., Roberts, K. D., Azad, M. A., Akter, J., Horne, A. S., Nation, R. L., Rogers, K. L., Thompson, P. E., Velkov, T., Li, J. (2014), ACS Bioconjug. Chem. 25, 750-760.