Clostridium difficile, an anaerobic, gram positive, spore-forming bacterium is the most common cause of antibiotic-associated diarrhea. Over the recent years, clostridium difficile infections (CDI) have become a cause of major concern due to the emergence of highly virulent strains such as NAP1/027. The antibiotic metronidazole (MTZ) is widely-used as the first line of treatment for mild to moderate CDI. However, it is associated with high relapse rates and performs poorly against severe NAP1/027 infections. This can be attributed to the high absorption (80-90%) of MTZ from the GI tract that leaves a low concentration of drug at the site of infection. Recently, we have shown that the tetramic acid reutericyclin and its analogs were highly effective against virulent C. difficile strains and that several of these analogs show poor intestinal absorption. Based on this, we explored whether hybridizing metronidazole with the tetramic acid moiety could improve its retention in the GI tract, whilst enhancing its anti-difficile action. We synthesized a series of metronidazole-tetramic acid hybrids and compared their activity to MTZ. In in vitro studies, these hybrids displayed comparable activity to MTZ, while in in vivo efficacy studies in the hamster model of CDI, several lead hybrids displayed better efficacy than MTZ. This improved efficacy is unlikely to be due to differences in mode of action as des-nitro hybrids lacked efficacy and MTZ and the hybrids induced similar cellular responses. However, in our Caco-2 cell permeability assay, these hybrids were less permeable than MTZ predicting lower intestinal absorption. Additional studies are underway including determination of compound pharmacokinetics in hamsters, efficacy in the mouse model of relapse and probing of cross-resistance.

Hybridization of metronidazole with natural product tetramic acids improves its antidifficile efficacy

249th National Meeting (2015)

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