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Understanding the activity of polyether ionophore lasalocid acid

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Lasalocid acid is a naturally occurring polyether ionophore, capable of reversibly binding metal cations, upon formation of a hydrophobic complex, which can diffuse across lipid membranes.1,2 Although the cation-transporting activity confers lasalocid acid potent activity against gram-positive bacterial strains,2 toxic side-effects are displayed in mammalian cells. To increase its prospects of becoming a safe human drug antibiotic, a detailed picture of the ionophore mechanism of ion transportation through lipid membranes must be acquired.
The project encompasses the chemical synthesis of an array of isotope-labelled lasalocid acid analogues, each bearing a CD3 group at strategic position on the scaffold. The molecular probes are then studied by solid-state 2H-NMR, a technique that reports on the molecular dynamics of each isotope label, as the ionophore becomes embedded on multilamellar lipid vesicles, thus providing an insight into the essential molecular motifs for cation transport.
The synthetic route towards the isotope-labelled probes is based on a degradation reassembly strategy on the natural ionophore.3 Lasalocid acid undergoes a series of chemical degradations to render the target positions “chemically accessible”, the deuterated motifs are inserted thereafter and, eventually, the entire scaffold is reconstructed. In addition, the envisioned synthetic strategy allows to functionalize the ionophore structure with biologically relevant chemical motifs, generating thus a library of artificial lasalocid acid analogues. Subsequent SAR studies - evaluation of antibiotic potency and mammalian cell viability - show that some of the novel derivatives display enhanced biological potential compared to the natural polyether ionophore.
1. Nakata, T. et al. J. Am. Chem. Soc., 1978, 100, 2933-2935.
2. Salvador, P. et al. Bioorg. Med. Chem., 2005, 13, 5181-5188.
3. Lin, S. et al. Nat. Chem., 2021, 13, 47–55.
Original languageEnglish
Publication year2022
Publication statusPublished - 2022

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