Issue 19, 2023

Targeting multidrug resistant Staphylococcus infections with bacterial histidine kinase inhibitors

Abstract

The emergence of drug-resistant bacteria, such as methicillin-resistant Staphylococcus aureus (MRSA), which are not susceptible to current antibiotics has necessitated the development of novel approaches and targets to tackle this growing challenge. Bacterial two-component systems (TCSs) play a central role in the adaptative response of bacteria to their ever-changing environment. They are linked to antibiotic resistance and bacterial virulence making the proteins of the TCSs, histidine kinases and response regulators, attractive for the development of novel antibacterial drugs. Here, we developed a suite of maleimide-based compounds that we evaluated against a model histidine kinase, HK853, in vitro and in silico. The most potent leads were then assessed for their ability to decrease the pathogenicity and virulence of MRSA, resulting in the identification of a molecule that decreased the lesion size caused by a methicillin-resistant S. aureus skin infection by 65% in a murine model.

Graphical abstract: Targeting multidrug resistant Staphylococcus infections with bacterial histidine kinase inhibitors

Supplementary files

Article information

Article type
Edge Article
Submitted
26 Sep 2022
Accepted
10 Apr 2023
First published
11 Apr 2023
This article is Open Access

All publication charges for this article have been paid for by the Royal Society of Chemistry
Creative Commons BY-NC license

Chem. Sci., 2023,14, 5028-5037

Targeting multidrug resistant Staphylococcus infections with bacterial histidine kinase inhibitors

A. Espinasse, M. Goswami, J. Yang, O. Vorasin, Y. Ji and E. E. Carlson, Chem. Sci., 2023, 14, 5028 DOI: 10.1039/D2SC05369A

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