Journal
MOLECULES
Volume 24, Issue 3, Pages -Publisher
MDPI
DOI: 10.3390/molecules24030553
Keywords
polymyxin; antibiotic resistance; antibiotics; nonapeptide; lipopeptide
Funding
- NHMRC [APP1005350, APP1045326, APP1139609, APP1059354]
- NIH [R21AI098731/R33AI098731]
- Wellcome Trust [094977/Z/10/Z, 104797/Z/14/Z]
Ask authors/readers for more resources
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-Thr(2)-Dab(3) lipodipeptide motif instead of the native FA-Dab(1)-Thr(2)-Dab(3) 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.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available