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Lookup NU author(s): Dr Oisín KavanaghORCiD
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© 2023 Elsevier Inc.Artificial transmembrane ion transporters have proposed applicability to medicinal chemistry, where perturbation of normal cellular homeostasis has already been shown to induce apoptosis in mammalian cells; however, this effect has not been observed in bacteria. In this study, we report the synthesis and structural characterization of a new class of fluorescent anionophores that effectively kill Gram-positive bacteria by disrupting normal Na+ and Cl− concentrations. The so-called “squindoles” take advantage of both NH and CH hydrogen-bonding interactions to bind chloride with high affinity and act as efficient anion transporters, as measured by lipid vesicle transport assays. The most active transporter shows potent inhibitory activity against Staphylococcus aureus (SA) and methicillin-resistant Staphylococcus aureus (MRSA). Cell-based assays and label-free quantitative proteomic profiling suggest that the mode of action is directly related to the anion-transport ability, whereby an influx of chloride into bacterial cells significantly affects their proteome and induces several known stress responses.
Author(s): Brennan LE, Kumawat LK, Piatek ME, Kinross AJ, McNaughton DA, Marchetti L, Geraghty C, Wynne C, Tong H, Kavanagh ON, O'Sullivan F, Hawes CS, Gale PA, Kavanagh K, Elmes RBP
Publication type: Article
Publication status: Published
Journal: Chem
Year: 2023
Volume: 9
Issue: 11
Pages: 3138-3158
Print publication date: 09/11/2023
Online publication date: 23/08/2023
Acceptance date: 02/04/2023
ISSN (print): 2451-9308
ISSN (electronic): 2451-9294
Publisher: Elsevier Inc.
URL: https://doi.org/10.1016/j.chempr.2023.07.014
DOI: 10.1016/j.chempr.2023.07.014
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