# Stk1 is required for BlaR1-mediated broad-spectrum β-lactam resistance in epidemic-causing strains of Staphylococcus aureus

## TL;DR

A new role for Stk1 in helping MRSA resist antibiotics is discovered, offering a potential new target for treating antibiotic-resistant infections.

## Contribution

The novel role of Stk1 in BlaR1-mediated antibiotic resistance in MRSA is identified.

## Key findings

- Phosphorylation of BlaR1 by Stk1 is essential for drug sensing and resistance in MRSA.
- Targeting Stk1 could enhance the effectiveness of β-lactam antibiotics against MRSA.
- A structural basis for Stk1 inhibition is presented for future drug development.

## Abstract

Sensory induction of mecA expression plays a pivotal role in mediating broad-spectrum β-lactam resistance (BBR) of MRSA. In contemporary MRSA isolates, sensory induction of BBR originates at the membrane-localized BlaR1, which, upon detection of β-lactam drugs, triggers a signal transduction cascade that promotes mecA induction. We hereby showed that phosphorylation of BlaR1, mediated through the serine-threonine kinase, Stk1, stabilizes its membrane spanning state and localization, allowing for proper drug sensing and subsequent signal transduction events to occur, culminating in mecA-mediated BBR. Our results demonstrated that targeting Stk1 could potentiate synthetic lethality to β-lactams in the majority of naturally isolated strains of MRSA. We also presented the structural and kinetic basis for a Stk1-inhibitor complex that could enable rational design of Stk1 directed anti-MRSA therapeutics in the future. Our results reveal a unique and hitherto unknown role of the STK signaling pathway in bacterial protein stabilization in the cytosolic membrane.