Gastrointestinal localization of metronidazole by a lactobacilli-inspired tetramic acid motif improves treatment outcomes in the hamster model of Clostridium difficile infection.
OBJECTIVE
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 < 0.05) than metronidazole in C. difficile-infected animals. Improved efficacy was not due to an alternative mode of action, as the leads retained the mode of action of metronidazole.


CONCLUSIONS
This study provides the clearest empirical evidence that the high absorption of metronidazole lowers treatment outcomes for CDI and suggests a role for the tetramic acid motif for colon-specific drug delivery. This approach also has the potential to lower systemic toxicity and drug interactions of nitroheterocyclic drugs for treating gastrointestine-specific diseases.
Department of Chemical Biology and Therapeutics, St Jude Children's Research Hospital, Memphis, TN 38105, USA.
Philip T
PT
Cherian
Department of Biology, University of Texas, Arlington, TX 76019, USA Center for Infectious and Inflammatory Diseases, Institute of Biosciences and Technology, Texas A&M Health Science Center, Houston, TX 77030, USA.
Xiaoqian
X
Wu
Department of Chemical Biology and Therapeutics, St Jude Children's Research Hospital, Memphis, TN 38105, USA.
Lei
L
Yang
Department of Chemical Biology and Therapeutics, St Jude Children's Research Hospital, Memphis, TN 38105, USA.
Jerrod S
JS
Scarborough
Department of Chemical Biology and Therapeutics, St Jude Children's Research Hospital, Memphis, TN 38105, USA Biomedical Sciences Program, Graduate Health Sciences, University of Tennessee Health Science Center, Memphis, TN 38163, USA.
Aman P
AP
Singh
Department of Biology, University of Texas, Arlington, TX 76019, USA.
Zahidul A
ZA
Alam
Department of Chemical Biology and Therapeutics, St Jude Children's Research Hospital, Memphis, TN 38105, USA.
Richard E
RE
Lee
Department of Biology, University of Texas, Arlington, TX 76019, USA Center for Infectious and Inflammatory Diseases, Institute of Biosciences and Technology, Texas A&M Health Science Center, Houston, TX 77030, USA Department of Microbial and Molecular Pathogenesis, Texas A&M Health Science Center, College of Medicine, Bryan, TX 77807, USA jhurdle@ibt.tamhsc.edu.
Julian G
JG
Hurdle
D000818:Animals; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D016360:Clostridioides difficile / Q000187:drug effects*; D003015:Clostridium Infections / Q000188:drug therapy*; D003106:Colon / Q000737:chemistry*; D004195:Disease Models, Animal; D008297:Male; D008647:Mesocricetus; D008795:Metronidazole / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D011760:Pyrrolidinones / Q000737:chemistry / Q000493:pharmacokinetics*; D013720:Tenuazonic Acid / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics; D016896:Treatment Outcome
D000900:Anti-Bacterial Agents; D011760:Pyrrolidinones; C416127:reutericyclin; D008795:Metronidazole; C009435:tetramic acid; D013720:Tenuazonic Acid