Expanding the antibacterial selectivity of polyether ionophore antibiotics through diversity-focused semisynthesis

Shaoquan Lin, Han Liu, Esben B. Svenningsen, Malene Wollesen, Kristian M. Jacobsen, Frederikke D. Andersen, Jaime Moyano-Villameriel, Christine N. Pedersen, Peter Nørby, Thomas Tørring, Thomas B. Poulsen*

*Corresponding author af dette arbejde

Publikation: Bidrag til tidsskrift/Konferencebidrag i tidsskrift /Bidrag til avisTidsskriftartikelForskningpeer review

Abstract

Polyether ionophores are complex natural products capable of transporting cations across biological membranes. Many polyether ionophores possess potent antimicrobial activity and a few selected compounds have the ability to target aggressive cancer cells. Nevertheless, ionophore function is believed to be associated with idiosyncratic cellular toxicity and, consequently, human clinical development has not been pursued. Here, we demonstrate that structurally novel polyether ionophores can be efficiently constructed by recycling components of highly abundant polyethers to afford analogues with enhanced antibacterial selectivity compared to a panel of natural polyether ionophores. We used classic degradation reactions of the natural polyethers lasalocid and monensin and combined the resulting fragments with building blocks provided by total synthesis, including halogen-functionalized tetronic acids as cation-binding groups. Our results suggest that structural optimization of polyether ionophores is possible and that this area represents a potential opportunity for future methodological innovation. [Figure not available: see fulltext.].

OriginalsprogEngelsk
TidsskriftNature Chemistry
Vol/bind13
Nummer1
Sider (fra-til)47-55
Antal sider9
ISSN1755-4330
DOI
StatusUdgivet - jan. 2021

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