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

Alexander, J. Andrew N.; Worrall, Liam J.; Hu, Jinhong; Vuckovic, Marija; Satishkumar, Nidhi; Poon, Raymond; Sobhanifar, Solmaz; Rosell, Federico I.; Jenkins, Joshua; Chiang, Daniel; Mosimann, Wesley A.; Chambers, Henry F.; Paetzel, Mark; Chatterjee, Som S.; Strynadka, Natalie C.  J.

doi:10.1038/s41586-022-05583-3

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

Journal Article · Wed Jan 04 04:00:00 EST 2023 · Nature (London)

DOI:https://doi.org/10.1038/s41586-022-05583-3· OSTI ID:2424189

; Worrall, Liam J.; Hu, Jinhong; Vuckovic, Marija; Satishkumar, Nidhi; Poon, Raymond; Sobhanifar, Solmaz; Rosell, Federico I.; ; Chiang, Daniel; Mosimann, Wesley A.; Chambers, Henry F.; ; Chatterjee, Som S.;

Abstract

Broad-spectrum β-lactam antibiotic resistance inStaphylococcus aureusis a global healthcare burden^1,2. 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, inducingblaZ(β-lactamase PC1) andmecA(β-lactam-resistant cell-wall transpeptidase PBP2a) expression^3–7. 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 incisbetween 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.

Research Organization:: Pacific Northwest National Laboratory (PNNL), Richland, WA (United States). Environmental Molecular Sciences Laboratory (EMSL)

Sponsoring Organization:: USDOE

DOE Contract Number:: AC05-76RL01830

OSTI ID:: 2424189

Journal Information:: Nature (London), Journal Name: Nature (London) Journal Issue: 7943 Vol. 613; ISSN 0028-0836

Publisher:: Nature Publishing Group

Country of Publication:: United States

Language:: English

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