Structure-Function Studies of Polymyxin B Lipononapeptides

Autor: Alejandra Gallardo-Godoy, Karl A. Hansford, Craig Muldoon, Bernd Becker, Alysha G. Elliott, Johnny X. Huang, Ruby Pelingon, Mark S. Butler, Mark A. T. Blaskovich, Matthew A. Cooper
Jazyk: angličtina
Rok vydání: 2019
Předmět:
Zdroj: Molecules, Vol 24, Iss 3, p 553 (2019)
Druh dokumentu: article
ISSN: 1420-3049
DOI: 10.3390/molecules24030553
Popis: 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.
Databáze: Directory of Open Access Journals
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