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J Org Chem. 2018 Jul 6;83(13):7173-7179. doi: 10.1021/acs.joc.8b00241. Epub 2018 Apr 10.

β-Lactam Biotransformations Activate Innate Immunity.

Oh J1,2, Patel J2,3, Park HB1,2, Crawford JM1,2,4.

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Department of Chemistry , Yale University , New Haven , Connecticut 06520 , United States.
Chemical Biology Institute , Yale University , West Haven , Connecticut 06516 , United States.
Department of Molecular, Cellular, and Developmental Biology , Yale University , New Haven , Connecticut 06520 , United States.
Department of Microbial Pathogenesis , Yale School of Medicine , New Haven , Connecticut 06536 , United States.


Antibiotics are widely prescribed to treat bacterial infections, but many of these drugs also affect patient immune responses. While the molecular mechanisms regulating these diverse immunomodulatory interactions are largely unknown, recent studies support two primary models: (1) antibiotics can alter immune function by directly interacting with human targets; and/or (2) antibiotics can indirectly affect immune responses via alteration of the human microbiota composition. Here, we describe results that could support a third model in which a nonimmunostimulatory antibiotic can be biotransformed by human microbiota members into an immunostimulatory product that lacks antibacterial activity. Specifically, we identified, characterized, and semisynthesized new biotransformation products derived from the β-lactams amoxicillin and ampicillin, antibiotics regularly prescribed in the clinic. The drug metabolism products were identified in bacterial cultures harboring β-lactamase, a common resistance determinant. One of the amoxicillin biotransformation products activated innate immunity, as assessed by NF-κB signaling in human leukemic monocytes, whereas amoxicillin itself exhibited no effect. Amoxicillin has previously been shown to have minimal long-term impact on human microbiota composition in clinical trial studies. Taken together, our results could support a broader immunomodulatory mechanism whereby antibiotics could indirectly regulate immune function in a stable, microbiome-dependent manner.

[Indexed for MEDLINE]

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