title: Diarylacylhydrazones: Clostridium-selective antibacterials with activity against stationary-phase cells.
abstract: Current antibiotics for treating Clostridium difficile infections (CDI), that is, metronidazole, vancomycin and more recently fidaxomicin, are mostly effective but treatment failure and disease relapse remain as significant clinical problems. The shortcomings of these agents are attributed to their low selectivity for C. difficile over normal gut microflora and their ineffectiveness against C. difficile spores. This Letter reports that certain diarylacylhydrazones identified during a high-throughput screening/counter-screening campaign show selective activity against two Clostridium species (C. difficile and Clostridium perfringens) over common gut commensals. Representative examples are shown to possess activity similar to vancomycin against clinical C. difficile strains and to kill stationary-phase C. difficile cells, which are responsible for spore production. Structure-activity relationships with additional synthesised analogues suggested a protonophoric mechanism may play a role in the observed activity/selectivity and this was supported by the well-known protonophore carbonyl cyanide m-chlorophenyl hydrazone (CCCP) showing selective anti-Clostridium effects and activity similar to diarylacylhydrazones against stationary-phase C. difficile cells. Two diarylacylhydrazones were shown to be non-toxic towards human FaDu and Hep G2 cells indicating that further studies with the class are warranted towards new drugs for CDI.
authors.affiliation: Antimicrobial Discovery Center, Department of Biology, Northeastern University, Boston, MA 02115, USA.
authors.forename: Chao
authors.initials: C
authors.lastname: Chen
authors.affiliation: Antimicrobial Discovery Center, Department of Biology, Northeastern University, Boston, MA 02115, USA.|School of Chemistry, University of Wollongong, NSW 2522, Australia.
authors.forename: Naveen K
authors.initials: NK
authors.lastname: Doll
authors.affiliation: Antimicrobial Discovery Center, Department of Biology, Northeastern University, Boston, MA 02115, USA.
authors.forename: Gabriele
authors.initials: G
authors.lastname: Casadei
authors.affiliation: School of Chemistry, University of Wollongong, NSW 2522, Australia.
authors.forename: John B
authors.initials: JB
authors.lastname: Bremner
authors.affiliation: Antimicrobial Discovery Center, Department of Biology, Northeastern University, Boston, MA 02115, USA.
authors.forename: Kim
authors.initials: K
authors.lastname: Lewis
authors.affiliation: School of Chemistry, University of Wollongong, NSW 2522, Australia.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Kelso
mesh_terms: D000617:Aminoglycosides / Q000737:chemistry / Q000494:pharmacology; D000900:Anti-Bacterial Agents / Q000737:chemistry* / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects / Q000502:physiology; D002460:Cell Line; D016360:Clostridioides difficile / Q000187:drug effects* / Q000502:physiology; D000077732:Fidaxomicin; D006801:Humans; D006835:Hydrazones / Q000737:chemistry* / Q000494:pharmacology*; D008826:Microbial Sensitivity Tests / Q000379:methods
chemical_list: D000617:Aminoglycosides; D000900:Anti-Bacterial Agents; D006835:Hydrazones; D000077732:Fidaxomicin
keywords: 2,4-DNP; 2,4-dinitrophenol; Antibacterial; CCCP; CDAD; CDI; Clostridium difficile; Clostridium difficile infection; Clostridium difficile-associated diarrhoea; DACC; DMSO; Data Analysis and Coordination Centre; Diarylacylhydrazone; FDA; HTS; MBC; MIC; NCI; NIH; National Cancer Institute; National Institutes of Health; PBS; PCP; PMC; Protonophore; Stationary phase cells; US Food and Drug Administration; carbonyl cyanide m-chlorophenylhydrazone; dimethyl sulfoxide; high-throughput screening; minimum bactericidal concentration; minimum inhibitory concentration; pentachlorophenol; phosphate buffered saline; pseudomembranous colitis