2. Academic Validation
  3. Structure-Function Studies of Polymyxin B Lipononapeptides

Structure-Function Studies of Polymyxin B Lipononapeptides

  • Molecules. 2019 Feb 2;24(3):553. doi: 10.3390/molecules24030553.
Alejandra Gallardo-Godoy 1,  Karl A Hansford 2,  Craig Muldoon 3,  Bernd Becker 4,  Alysha G Elliott 5,  Johnny X Huang 6,  Ruby Pelingon 7,  Mark S Butler 8,  Mark A T Blaskovich 9,  Matthew A Cooper 10
Affiliations

Affiliations

  • 1 Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland 4072, Australia. a.gallardogodoy@uq.edu.au.
  • 2 Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland 4072, Australia. k.hansford@uq.edu.au.
  • 3 Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland 4072, Australia. cmouldy@yahoo.com.au.
  • 4 Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland 4072, Australia. bbeckerr@gmail.com.
  • 5 Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland 4072, Australia. a.elliott@imb.uq.edu.au.
  • 6 Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland 4072, Australia. johnny.xiao.huang@gmail.com.
  • 7 Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland 4072, Australia. r.pelingon@imb.uq.edu.au.
  • 8 Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland 4072, Australia. m.butler5@uq.edu.au.
  • 9 Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland 4072, Australia. m.blaskovich@uq.edu.au.
  • 10 Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland 4072, Australia. m.cooper@uq.edu.au.
PMID: 30717415 DOI: 10.3390/molecules24030553
Abstract

The emerging threat of infections caused by highly drug-resistant bacteria has prompted a resurgence in the use of the lipodecapeptide Antibiotics polymyxin B and colistin as last resort therapies. Given the emergence of resistance to these drugs, there has also been a renewed interest in the development of next generation polymyxins with improved therapeutic indices and spectra of action. We report structure-activity studies of 36 polymyxin lipononapeptides structurally characterised by an exocyclic FA-Thr²-Dab³ lipodipeptide motif instead of the native FA-Dab¹-Thr²-Dab³ tripeptide motif found in polymyxin B, removing one of the positively charged residues believed to contribute to nephrotoxicity. The compounds were prepared by solid phase synthesis using an on-resin cyclisation approach, varying the fatty acid and the residues at position 2 (P2), P3 and P4, then assessing antimicrobial potency against a panel of Gram-negative bacteria, including polymyxin-resistant strains. Pairwise comparison of N-acyl nonapeptide and decapeptide analogues possessing different fatty acids demonstrated that antimicrobial potency is strongly influenced by the N-terminal L-Dab-1 residue, contingent upon the fatty acid. This study highlights that antimicrobial potency may be retained upon truncation of the N-terminal L-Dab-1 residue of the native exocyclic lipotripeptide motif found in polymyxin B. The strategy may aid in the design of next generation polymyxins.

Keywords

antibiotic resistance; antibiotics; lipopeptide; nonapeptide; polymyxin.

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