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An oxidation-sensing mechanism is used by the global regulator MgrA in Staphylococcus aureus

Abstract

Staphylococcus aureus is a human pathogen responsible for most wound and hospital-acquired infections1,2. The protein MgrA is both an important virulence determinant during infection and a regulator of antibiotic resistance in S. aureus3,4,5,6,7. The crystal structure of the MgrA homodimer, solved at 2.86 Å, indicates the presence of a unique cysteine residue located at the interface of the protein dimer. We discovered that this cysteine residue can be oxidized by various reactive oxygen species, such as hydrogen peroxide and organic hydroperoxide. Cysteine oxidation leads to dissociation of MgrA from DNA and initiation of signaling pathways that turn on antibiotic resistance in S. aureus. The oxidation-sensing mechanism is typically used by bacteria to counter challenges of reactive oxygen and nitrogen species8,9,10,11,12. Our study reveals that in S. aureus, MgrA adopts a similar mechanism but uses it to globally regulate different defensive pathways.

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Figure 1: Effect of the mgrA mutation on the virulence of S. aureus as tested using the murine abscess model of infection.
Figure 2: Crystal structure of MgrA.
Figure 3: Oxidation of Cys12 dissociates MgrA from DNA in vitro.
Figure 4: Monitoring in vivo effects of MgrA oxidation.

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Acknowledgements

We thank D.M. Missiakas for the gift of mgrA mutant, K. DeBord for help with mouse experiments and X. Yang for computer maintenance and assistance. We thank the beamline personnel at BioCARS of the Advanced Photon Source at Argonne National Laboratory for their help. This work was supported by the University of Chicago, the Searle Scholars Program (C.H.) and a Burroughs Wellcome Fund Interfaces (#1001774 to P.R.C. and E.M.D.). Use of the Advanced Photon Source was supported by the US Department of Energy, Basic Energy Sciences, Office of Science, under Contract No. W-31-109-Eng-38. Use of the BioCARS Sector 14 was supported by the US National Institutes of Health, National Center for Research Resources, under grant number RR07707. Work in the laboratory of O. Schneewind is supported by grants from the US National Institutes of Allergy and Infectious Diseases, Infectious Diseases Branch AI38979 and AI52474.

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Contributions

C.H. designed experimental strategies with the help of O.S. and P.A.R. P.R.C. performed all experiments with the help of T.B. (microbiology), W.A.W. (microbiology) and E.M.D. (crystallography).

Note: Supplementary information is available on the Nature Chemical Biology website.

Corresponding author

Correspondence to Chuan He.

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Supplementary information

Supplementary Fig. 1

SDS-PAGE gel of the MgrA, MgrAΔ and MgrA C12S proteins expressed in BL21(DE3). (PDF 204 kb)

Supplementary Fig. 2

Density map based on prerefinement solvent flattened phases from RESOLVE. (PDF 680 kb)

Supplementary Fig. 3

Molecular modeling of MgrA–DNA complex. (PDF 402 kb)

Supplementary Fig. 4

Sequence alignment of MgrA with B. subtilus OhrR. (PDF 396 kb)

Supplementary Table 1

X-ray data and refinement statistics. (PDF 80 kb)

Supplementary Table 2

An example of the 96-well plate sensitivity assay. (PDF 115 kb)

Supplementary Methods (PDF 240 kb)

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Chen, P., Bae, T., Williams, W. et al. An oxidation-sensing mechanism is used by the global regulator MgrA in Staphylococcus aureus. Nat Chem Biol 2, 591–595 (2006). https://doi.org/10.1038/nchembio820

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