Potent antimicrobial effect induced by disruption of chloride homeostasis

Brennan, Luke E.; Kumawat, Lokesh K.; Piatek, Magdalena E.; Kinross, Airlie J.; McNaughton, Daniel A.; Marchetti, Luke; Geraghty, Conor; Wynne, Conor; Tong, Hua; Kavanagh, Oisín N.; O’Sullivan, Finbarr; Hawes, Chris S.; Gale, Philip A.; Kavanagh, Kevin; Elmes, Robert B.P.

Abstract

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 as-says 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.

Citation

Brennan, L. E., Kumawat, L. K., Piatek, M. E., Kinross, A. J., McNaughton, D. A., Marchetti, L., Geraghty, C., Wynne, C., Tong, H., Kavanagh, O. N., O’Sullivan, F., Hawes, C. S., Gale, P. A., Kavanagh, K., & Elmes, R. B. (in press). Potent antimicrobial effect induced by disruption of chloride homeostasis. Chem, 9(11), 3138-3158. https://doi.org/10.1016/j.chempr.2023.07.014

• Journal Article Type: Article
• Acceptance Date: Jul 24, 2023
• Online Publication Date: Aug 23, 2023
• Deposit Date: Nov 7, 2023
• Publicly Available Date: Aug 24, 2024
• Journal: Chem
• Print ISSN: 2451-9308
• Electronic ISSN: 2451-9294
• Publisher: Elsevier
• Peer Reviewed: Peer Reviewed
• Volume: 9
• Issue: 11
• Pages: 3138-3158
• DOI: https://doi.org/10.1016/j.chempr.2023.07.014
• Keywords: Materials Chemistry; Biochemistry (medical); General Chemical Engineering; Environmental Chemistry; Biochemistry; General Chemistry
• Public URL: https://keele-repository.worktribe.com/output/625881
• Publisher URL: https://www.sciencedirect.com/science/article/abs/pii/S2451929423003650?via%3Dihub
• Additional Information: This article is maintained by: Elsevier; Article Title: Potent antimicrobial effect induced by disruption of chloride homeostasis; Journal Title: Chem; CrossRef DOI link to publisher maintained version: https://doi.org/10.1016/j.chempr.2023.07.014; Content Type: article; Copyright: © 2023 Elsevier Inc.