ß-Lactam Biotransformations Activate Innate Immunity.
J Org Chem
; 83(13): 7173-7179, 2018 07 06.
Article
em En
| MEDLINE
| ID: mdl-29616809
ABSTRACT
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 ß-lactams amoxicillin and ampicillin, antibiotics regularly prescribed in the clinic. The drug metabolism products were identified in bacterial cultures harboring ß-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.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Biotransformação
/
Beta-Lactamas
/
Imunidade Inata
Idioma:
En
Revista:
J Org Chem
Ano de publicação:
2018
Tipo de documento:
Article
País de afiliação:
Estados Unidos