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Small-molecule targeting of a diapophytoene desaturase inhibits S. aureus virulence

Abstract

The surge of antibiotic resistance in Staphylococcus aureus has created a dire need for innovative anti-infective agents that attack new targets, to overcome resistance. In S. aureus, carotenoid pigment is an important virulence factor because it shields the bacterium from host oxidant killing. Here we show that naftifine, a US Food and Drug Administration (FDA)-approved antifungal drug, blocks biosynthesis of carotenoid pigment at nanomolar concentrations. This effect is mediated by competitive inhibition of S. aureus diapophytoene desaturase (CrtN), an essential enzyme for carotenoid pigment synthesis. We found that naftifine attenuated the virulence of a variety of clinical S. aureus isolates, including methicillin-resistant S. aureus (MRSA) strains, in mouse infection models. Specifically, we determined that naftifine is a lead compound for potent CrtN inhibitors. In sum, these findings reveal that naftifine could serve as a chemical probe to manipulate CrtN activity, providing proof of concept that CrtN is a druggable target against S. aureus infections.

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Figure 1: Naftifine has antivirulence properties against S. aureus Newman.
Figure 2: Naftifine treatment resulted in inhibition of the in vivo function of CrtN.
Figure 3: Naftifine is a CrtN inhibitor.
Figure 4: CrtN is important for S. aureus pathogenesis.
Figure 5: Naftifine blocks the virulence of MRSA strains.

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Acknowledgements

We thank M. Wu for helpful discussion, S.F. Reichard for editing the manuscript, and F. Götz (University of Tübingen) for providing the S. carnosus strains TM300pTX15 and TM300pTXcrtMN. This work was supported by the National Natural Science Foundation of China (21472207 and 31270126 to L.L.; 21222211 and 91313303 to J.L.), Hundred Talents Program of the Chinese Academy of Sciences (L.L.), Shanghai Institute of Materia Medica Foundation (CASIMM0120152018 to L.L.), Shanghai Municipal Education Commission and Shanghai Education Development Foundation (14SG28 to J.L.) and Foundation of the State Key Laboratory of Drug Research (SIMM1302KF-01 to J.L.). We acknowledge the National Science and Technology Major Project “Key New Drug Creation and Manufacturing Program” (2013ZX09507-004 to C.-G.Y.) and Shanghai Committee of Science and Technology (12ZR1453200 to F.C.).

Author information

Authors and Affiliations

Authors

Contributions

F.C. performed the biological experiments and drafted the biology part of the manuscript. H.D. performed the biological experiments. Y.W. synthesized naftifine derivatives. F.L. and N.Z. performed one-dimensional NMR spectroscopy analysis. Q.C., B.X., X.Z. and N.Y. participated in the mouse infection experiment; G.L. and C.-G.Y. contributed to protein purification; Y.X. and H.J. contributed to data analysis. J.L. designed the chemical synthesis and drafted the chemistry part of the manuscript. L.L. conceived the study, designed the biological experiments and wrote the manuscript. All authors contributed to interpretation of data, and read and approved the final manuscript.

Corresponding authors

Correspondence to Jian Li or Lefu Lan.

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Competing interests

L.L., J.L., F.C., Y.W. and H.J. are named inventors of pending patent applications (CN201410190672 and PCT/CN2014/079565, to the Chinese Patent Office) related to the work described.

Supplementary information

Supplementary Text and Figures

Supplementary Results, Supplementary Tables 1 and 2 and Supplementary Figures 1–18 (PDF 3365 kb)

Supplementary Data Set 1

A collection of 412 marked drugs used for the screening in this study (PDF 528 kb)

Supplementary Note

Synthetic Procedures (PDF 3633 kb)

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Chen, F., Di, H., Wang, Y. et al. Small-molecule targeting of a diapophytoene desaturase inhibits S. aureus virulence. Nat Chem Biol 12, 174–179 (2016). https://doi.org/10.1038/nchembio.2003

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