Structural basis of broad-spectrum β-lactam resistance in Staphylococcus aureus

J. Andrew N. Alexander, Liam J. Worrall, Jinhong Hu, Marija Vuckovic, Nidhi Satishkumar, Raymond Poon, Solmaz Sobhanifar, Federico I. Rosell, Joshua Jenkins, Daniel Chiang, Wesley A. Mosimann, Henry F. Chambers, Mark Paetzel, Som S. Chatterjee and Natalie C. J. Strynadka ()
Additional contact information
J. Andrew N. Alexander: The University of British Columbia
Liam J. Worrall: The University of British Columbia
Jinhong Hu: The University of British Columbia
Marija Vuckovic: The University of British Columbia
Nidhi Satishkumar: University of Maryland
Raymond Poon: University of Maryland
Solmaz Sobhanifar: The University of British Columbia
Federico I. Rosell: The University of British Columbia
Joshua Jenkins: The University of British Columbia
Daniel Chiang: Simon Fraser University
Wesley A. Mosimann: The University of British Columbia
Henry F. Chambers: University of California, San Francisco
Mark Paetzel: Simon Fraser University
Som S. Chatterjee: University of Maryland
Natalie C. J. Strynadka: The University of British Columbia

Nature, 2023, vol. 613, issue 7943, 375-382

Abstract: Abstract Broad-spectrum β-lactam antibiotic resistance in Staphylococcus aureus is a global healthcare burden1,2. In clinical strains, resistance is largely controlled by BlaR13, a receptor that senses β-lactams through the acylation of its sensor domain, inducing transmembrane signalling and activation of the cytoplasmic-facing metalloprotease domain4. The metalloprotease domain has a role in BlaI derepression, inducing blaZ (β-lactamase PC1) and mecA (β-lactam-resistant cell-wall transpeptidase PBP2a) expression3–7. Here, overcoming hurdles in isolation, we show that BlaR1 cleaves BlaI directly, as necessary for inactivation, with no requirement for additional components as suggested previously8. Cryo-electron microscopy structures of BlaR1—the wild type and an autocleavage-deficient F284A mutant, with or without β-lactam—reveal a domain-swapped dimer that we suggest is critical to the stabilization of the signalling loops within. BlaR1 undergoes spontaneous autocleavage in cis between Ser283 and Phe284 and we describe the catalytic mechanism and specificity underlying the self and BlaI cleavage. The structures suggest that allosteric signalling emanates from β-lactam-induced exclusion of the prominent extracellular loop bound competitively in the sensor-domain active site, driving subsequent dynamic motions, including a shift in the sensor towards the membrane and accompanying changes in the zinc metalloprotease domain. We propose that this enhances the expulsion of autocleaved products from the active site, shifting the equilibrium to a state that is permissive of efficient BlaI cleavage. Collectively, this study provides a structure of a two-component signalling receptor that mediates action—in this case, antibiotic resistance—through the direct cleavage of a repressor.

Date: 2023
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DOI: 10.1038/s41586-022-05583-3

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