Structural highlights
Publication Abstract from PubMedSensory induction of mecA expression plays a pivotal role in mediating broad-spectrum beta-lactam resistance (BBR) of MRSA. In contemporary MRSA isolates, sensory induction of BBR originates at the membrane-localized BlaR1, which, upon detection of beta-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 beta-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. Stk1 is required for BlaR1-mediated broad-spectrum beta-lactam resistance in epidemic-causing strains of Staphylococcus aureus.,Chatterjee S, Poon R, Satishkumar N, Mosimann W, Hayatnagarkar V, Hemmadi V, Kuhn S, Chatterjee A, Worrall L, Manes N, Alexander JA, Lack J, Chambers H, Nita-Lazar A, Strynadka N Res Sq [Preprint]. 2026 Jan 12:rs.3.rs-8331258. doi: 10.21203/rs.3.rs-8331258/v1. PMID:41743328[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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