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.
Highlights
The polymyxins (Pmx) are natural product polycationic lipodecapeptides produced by Paenibacillus polymyxa (Figure 1), exemplified by polymyxin B 1 (PmxB) and E 2 [1,2,3,4]
A total of 36 compounds were synthesized in this study, with the structures presented in Tables 1–3 and Table S1 (Supporting previously [33,36,37,38,39]), with the structures presented in Tables 1–3 and Table S1
On-resin cyclisation has been reported using diaminobutyric acid (Dab)-9 as the anchoring point, which was attached hand, on-resin cyclisation has been reported using Dab-9 as the anchoring point, which was attached to the resin via the Nγγ -amino group of the side chain [42]
Summary
Received: 21 December 2018; Accepted: 27 January 2019; Published: 2 February 2019
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