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The anti-inflammatory drug mesalamine targets bacterial polyphosphate accumulation

Nature Microbiology volume 2, Article number: 16267 (2017) Cite this article

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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.

Kinetic studies using purified E. coli PPK confirmed that mesalamine inhibits PPK in vitro by increasing the Michaelis constant (Km) of PPK for adenosine triphosphate (ATP) and lowering its inhibitory constant (Ki) for substrate inhibition by ATP (Fig. 1b). To determine whether mesalamine treatment had any effect on the in vivo activity of PPK, we measured cellular polyP levels in a variety of PPK-containing pathogens following a shift to low-phosphate medium, a condition known to induce polyP accumulation5. Each of the tested strains showed a 50–60% reduction in polyP levels when the nutrient shift was conducted in the presence of non-lethal doses of mesalamine (Fig. 1c–e and Supplementary Fig. 2a). Similar results were obtained when we treated bacteria cultivated from the caecal content of healthy mice (Fig. 1f). These results suggested that mesalamine directly affects bacterial polyP levels and also works at concentrations lower than those needed to significantly inhibit purified PPK in vitro. Because polyP regulates its own production by inducing the transcription of rpoS, the gene encoding the general stress response sigma factor RpoS that also controls ppk expression6, we tested transcript levels of rpoS and ppk in wild-type uropathogenic Escherichia coli (UPEC) upon nutrient shift in the absence and presence of mesalamine. Indeed, we found that mesalamine significantly reduced both rpoS and ppk expression (Fig. 1g, top and middle panels) while not altering rpoS expression levels in nutrient-shifted ppk-deficient strains (Fig. 1g, bottom panel). These results suggest that mesalamine attenuates the in vivo feedback regulation of polyP via rpoS, probably contributing to the more pronounced effect of mesalamine treatment on in vivo polyP levels. Future mechanistic studies are needed to reveal the mechanism of mesalamine action on PPK and explore the possibility that bacteria themselves might convert mesalamine into a more PPK-reactive compound7.

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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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  1. Michael J. Gray

    Present address: †Present address: Department of Microbiology, University of Alabama, 656 Bevill Biomedical Research Building, 845 19th Street South, Birmingham, Alabama 35294, USA.,

Authors and Affiliations

  1. Department of Molecular, Cellular, and Developmental Biology, University of Michigan, Ann Arbor, 48109, Michigan, USA

    Jan-Ulrik Dahl, Michael J. Gray, Daphne Bazopoulou, Francois Beaufay, Justine Lempart & Ursula Jakob

  2. Department of Pharmaceutical Sciences, University of Michigan, Ann Arbor, 48109, Michigan, USA

    Mark J. Koenigsknecht, Ying Wang & Duxin Sun

  3. Department of Internal Medicine, Division of Gastroenterology, University of Michigan, Ann Arbor, 48109, Michigan, USA

    Jason R. Baker & William L. Hasler

  4. Department of Internal Medicine/Division of Infectious Diseases & Department of Microbiology and Immunology, The University of Michigan Medical School, Ann Arbor, 48109, Michigan, USA

    Vincent B. Young

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Contributions

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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Supplementary Information

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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