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The anti-inflammatory drug mesalamine targets bacterial polyphosphate accumulation

Abstract

Mesalamine serves as the gold standard in treating ulcerative colitis. However, its precise mechanism(s) of action remains unclear. Here, we show that mesalamine treatment rapidly decreases polyphosphate levels in diverse bacteria, including members of the human gut microbiome. This decrease sensitizes bacteria towards oxidative stress, reduces colonization and attenuates persister cell and biofilm formation, suggesting that mesalamine aids in diminishing the capacity of bacteria to persist within chronically inflamed environments.

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Figure 1: Mesalamine mimics ppk mutant phenotypes.
Figure 2: Mesalamine reduces polyP levels in gut microbiota.

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Acknowledgements

The authors acknowledge the University of Michigan Center for Chemical Genomics for assistance with high-throughput screening. The authors thank K. Vendrov for killing the mice and preparing caecal samples, D. Knoefler for help with the statistical analyses and C.M. Cremers for help with establishing the assay for quantification of steady-state polyP levels. The authors thank L. Xie and K. Wan for their help with the purification of PPX and PPK, respectively. This work was funded by the National Institute of Health grants GM065318 (to U.J.), AI090871 and AI24255 (to V.B.Y.) and by FDA grants HHSF223201000082C and HHSF223201300460A (to D.S.). Clinical samples were collected with help from the Michigan Institute for Clinical & Health Research (MICHR) NIH grant UL1TR000433. J.-U.D. is supported by a postdoctoral fellowship from the Deutsche Forschungsgemeinschaft grant DA1697/1-1.

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J.-U.D., M.J.G., D.B. and F.B. designed and carried out experiments. M.J.K., Y.W., J.R.B., W.L.H. and D.S. designed and carried out the biopsies of the human GI samples and the subsequent analyses of mesalamine concentrations. J.-U.D., M.J.G. and U.J. conceived the study, interpreted the results and wrote the manuscript. V.B.Y. was involved in conceiving the experiments for detection of polyP in the caecal contents of mice. J.L. was involved in establishing the assay for quantification of steady-state polyP levels.

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Correspondence to Ursula Jakob.

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The authors declare no competing financial interests.

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Supplementary Figures 1 and 2, Supplementary Table 1, Supplementary Notes and Discussion, Supplementary Methods and Supplementary References. (PDF 2242 kb)

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Dahl, JU., Gray, M., Bazopoulou, D. et al. The anti-inflammatory drug mesalamine targets bacterial polyphosphate accumulation. Nat Microbiol 2, 16267 (2017). https://doi.org/10.1038/nmicrobiol.2016.267

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