title: Action of nitroheterocyclic drugs against Clostridium difficile.
abstract: The nitroheterocyclic classes of drugs have a long history of use in treating anaerobic infections, as exemplified by metronidazole as a first-line treatment for mild-to-moderate Clostridium difficile infection (CDI). Since direct comparisons of the three major classes of nitroheterocyclic drugs (i.e. nitroimidazole, nitazoxanide and nitrofurans) and nitrosating agents against C. difficile are under-examined, in this study their actions against C. difficile were compared. Results show that whilst transient resistance occurs to metronidazole and nitazoxanide, stable resistance arises to nitrofurans upon serial passage. All compounds killed C. difficile at high concentrations in addition to the host defence nitrosating agent S-nitrosoglutathione (GSNO). This suggests that GSNO killing of C. difficile contributes to its efficacy in murine CDI. Although nitric oxide production could not be detected for the nitroheterocyclic drugs, the cellular response to metronidazole and nitrofurans has some overlap with the response to GSNO, causing significant upregulation of the hybrid-cluster protein Hcp that responds to nitrosative stress. These findings provide new insights into the action of nitroheterocyclic drugs against C. difficile.
authors.affiliation: Department of Biology, University of Texas at Arlington, Arlington, TX 76019, USA.
authors.forename: Manish
authors.initials: M
authors.lastname: Kumar
authors.affiliation: Department of Biology, University of Texas at Arlington, Arlington, TX 76019, USA.
authors.forename: Sudip
authors.initials: S
authors.lastname: Adhikari
authors.affiliation: Department of Biology, University of Texas at Arlington, Arlington, TX 76019, USA. Electronic address: hurdle@uta.edu.
authors.forename: Julian G
authors.initials: JG
authors.lastname: Hurdle
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D016360:Clostridioides difficile / Q000187:drug effects*; D024881:Drug Resistance, Bacterial; D004361:Drug Tolerance; D020869:Gene Expression Profiling; D050296:Microbial Viability / Q000187:drug effects; D009154:Mutation; D009574:Nitro Compounds; D009581:Nitrofurans / Q000494:pharmacology*; D009593:Nitroimidazoles / Q000494:pharmacology*; D009603:Nitroso Compounds / Q000633:toxicity; D012692:Serial Passage; D013312:Stress, Physiological; D013844:Thiazoles / Q000494:pharmacology*
chemical_list: D000900:Anti-Bacterial Agents; D009574:Nitro Compounds; D009581:Nitrofurans; D009593:Nitroimidazoles; D009603:Nitroso Compounds; D013844:Thiazoles; C041747:nitazoxanide
keywords: Anti-Clostridium difficile action; Nitazoxanide; Nitrofurans; Nitroimidazole; Nitrosative stress