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Restoring susceptibility to β-lactam antibiotics in methicillin-resistant Staphylococcus aureus

Nature Chemical Biology (2024)Cite this article

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Abstract

Infections by Staphylococcus aureus have been treated historically with β-lactam antibiotics. However, these antibiotics have become obsolete in methicillin-resistant S. aureus by acquisition of the bla and mec operons. The presence of the β-lactam antibiotic is detected by the sensor domains of BlaR and/or MecR, and the information is transmitted to the cytoplasm, resulting in derepression of the antibiotic-resistance genes. We hypothesized that inhibition of the sensor domain would shut down this response system, and β-lactam susceptibility would be restored. An in silico search of 11 million compounds led to a benzimidazole-based hit and, ultimately, to the boronate 4. The X-ray structure of 4 is covalently engaged with the active-site serine of BlaR. Compound 4 potentiates by 16- to 4,096-fold the activities of oxacillin and of meropenem against methicillin-resistant S. aureus strains. The combination of 4 with oxacillin or meropenem shows efficacy in infected mice, validating the strategy.

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Fig. 1: Schematic for the activation of BlaR.
Fig. 2: Fluorescence assay to identify potential BlaR inhibitors and their binding modes to the sensor domain of BlaR.
Fig. 3: Analysis of compound 4 binding to BlaR sensor domain.
Fig. 4: Interactions of compound 4 and cefepime with the extracellular loop EL1 of BlaR.
Fig. 5: Growth curves with specific anti-sense RNA in the COL strain background.
Fig. 6: In vitro and in vivo activities of compound 4 in combination with OXA or MEM.

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Data availability

The data that support the findings of this work are available in this Article and its Supplementary Information. General synthetic procedure; synthetic experimental procedures and characterization data; X-ray data collection method; crystal data and structure refinement for 2 and 4 and cefepime; NMR spectra for representative compounds, extended potential and MIC data, checkerboard and time-kill assays are included in Supplementary Information. The crystallographic parameters for structures of BlaR:2, BlaR:4 and BlaR:cefepime complexes have been deposited in the Protein Data Bank under accession codes 8C0S, 8C0P and 8CF3, respectively. Source data are provided with this paper.

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Acknowledgements

We thank the staff from the XALOC beamline at ALBA synchrotron facility for their help during crystallographic data collection. J.Y. and A.M.E.-A. are Ruth L. Kirschtein National Research Service Award Fellows of the Chemistry–Biochemistry–Biology Interface (CBBI) Program at the University of Notre Dame supported by training grant T32 GM145773. We thank BEI Resources, NIAID, NIH for strains of MSSA and MRSA. The anti-sense strains were generous gifts of T. Roemer of Merck. We also thank R. Bonomo for the kind gift of samples of vaborbactam and taniborbactam. This work was supported by a grant from the National Institutes of Health (AI104987) in the USA. The work in Spain was supported by grants from the Spanish Ministry of Science and Innovation (PID2020-115331GB-I00) and from the Swiss National Science Foundation (CRSII5_198737/1, SINERGIA) to J.A.H.

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  1. These authors contributed equally: Biruk T. Birhanu, Vega Miguel-Ruano.

Authors and Affiliations

  1. Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN, USA

    Van T. Nguyen, Biruk T. Birhanu, Choon Kim, Jingdong Yang, Amr M. El-Araby, Valerie A. Schroeder, Neha Rana, Safaa Sader, Caitlyn A. Thomas, Rhona Feltzer, Mijoon Lee, Jed F. Fisher, Mayland Chang & Shahriar Mobashery

  2. Department of Crystallography and Structural Biology, Instituto de Química-Física ‘Blas Cabrera’, Consejo Superior de Investigaciones Científicas, Madrid, Spain

    Vega Miguel-Ruano, Mayte Batuecas, Eva Jiménez-Faraco, Alejandra Alba & Juan A. Hermoso

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Contributions

V.T.N. synthesized compounds. C.K. produced fluorescent plasmids. V.T.N. and C.K. performed MIC, potentiation, fluorescence and anti-sense assays. B.T.B. conducted time-kill assays. B.T.B. and J.Y. conducted the mouse neutropenic thigh infection studies. J.Y. performed the PK study and toxicity assay. M.L. performed mass spectrometry experiments. A.M.E.-A performed the binding experiments. S.S. and A.M.E.-A. performed MD simulations. N.R. performed virtual screening of compound libraries. R.F. and C.A.T purified the BlaR protein. V.M.-R., M.B., E.J.-F., A. A. and J.A.H. obtained and analyzed X-ray crystal structures. V.M.-R. and J.A.H performed computational modeling. B.T.B. and V.A.S. conducted the in-life portion of the PK and neutropenic thigh infection studies. M.C. directed the time-kill assays and in vivo studies. S.M. directed the project. S.M., J.F.F., M.C., J.A.H., V.T.N., B.T.B. and C.K. prepared the manuscript. All authors approved the final version of the manuscript.

Corresponding author

Correspondence to Shahriar Mobashery.

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Nature Chemical Biology thanks Gemma Nixon, Alejandro Vila and the other, anonymous, reviewers for their contribution to the peer review of this work.

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Supplementary information

Supplementary Information

Supplementary Figs. 1–16, Tables 1 and 2 and Notes 1–6.

Reporting Summary

Supplementary Video 1

MD simulations of BlaR and compound 4.

Supplementary Video 2

MD simulations of wild-type BlaR.

Supplementary Video 3

MD simulation of mutant BlaR and compound 4.

Supplementary Data 1

Raw fluorescence intensity data for Supplemenary Fig. 7.

Supplementary Data 2

Inhibition data for Supplemenary Fig. 8.

Supplementary Data 3

Raw data for time-kill assay for Supplementary Fig. 14.

Supplementary Data 4

Raw PK data for Supplementary Fig. 15.

Supplementary Data 5

Raw data and statistical analysis for in vivo experiment for Supplementary Fig. 16.

Source data

Source Data Fig. 3

Raw data for binding affinity and kinetic analysis.

Source Data Fig. 5

Raw data for inhibitions of PBPs.

Source Data Fig. 6

Raw data for in vivo experiment.

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Nguyen, V.T., Birhanu, B.T., Miguel-Ruano, V. et al. Restoring susceptibility to β-lactam antibiotics in methicillin-resistant Staphylococcus aureus. Nat Chem Biol (2024). https://doi.org/10.1038/s41589-024-01688-0

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