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10.1093/jac/dkv231

http://scihub22266oqcxt.onion/10.1093/jac/dkv231
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C4677261!4677261!26286574
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suck abstract from ncbi


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pmid26286574      J+Antimicrob+Chemother 2015 ; 70 (11): 3061-9
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  • Gastrointestinal localization of metronidazole by a lactobacilli-inspired tetramic acid motif improves treatment outcomes in the hamster model of Clostridium difficile infection #MMPMID26286574
  • Cherian PT; Wu X; Yang L; Scarborough JS; Singh AP; Alam ZA; Lee RE; Hurdle JG
  • J Antimicrob Chemother 2015[Nov]; 70 (11): 3061-9 PMID26286574show ga
  • Objectives: Metronidazole, a mainstay treatment for Clostridium difficile infection (CDI), is often ineffective for severe CDI. Whilst this is thought to arise from suboptimal levels of metronidazole in the colon due to rapid absorption, empirical validation is lacking. In contrast, reutericyclin, an antibacterial tetramic acid from Lactobacillus reuteri, concentrates in the gastrointestinal tract. In this study, we modified metronidazole with reutericyclin's tetramic acid motif to obtain non-absorbed compounds, enabling assessment of the impact of pharmacokinetics on treatment outcomes. Methods: A series of metronidazole-bearing tetramic acid substituents were synthesized and evaluated in terms of anti-C. difficile activities, gastric permeability, in vivo pharmacokinetics, efficacy in the hamster model of CDI and mode of action. Results: Most compounds were absorbed less than metronidazole in cell-based Caco-2 permeability assays. In hamsters, lead compounds compartmentalized in the colon rather than the bloodstream with negligible levels detected in the blood, in direct contrast with metronidazole, which was rapidly absorbed into the blood and was undetectable in caecum. Accordingly, four leads were more efficacious (P?
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