Targeting multidrug resistant <i>Staphylococcus</i> infections with bacterial histidine kinase inhibitors

Abstract

The emergence of drug-resistant bacteria, such as methicillin-resistant <i>Staphylococcus aureus</i> (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, <i>in vitro</i> and <i>in silico</i>. 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 <i>S. aureus</i> skin infection by 65% in a murine model.