title: Reprofiled anthelmintics abate hypervirulent stationary-phase Clostridium difficile.
abstract: Prolonged use of broad-spectrum antibiotics disrupts the indigenous gut microbiota, which consequently enables toxigenic Clostridium difficile species to proliferate and cause infection. The burden of C. difficile infections was exacerbated with the outbreak of hypervirulent strains that produce copious amounts of enterotoxins and spores. In recent past, membrane-active agents have generated a surge of interest due to their bactericidal property with a low propensity for resistance. In this study, we capitalized on the antimicrobial property and low oral bioavailability of salicylanilide anthelmintics (closantel, rafoxanide, niclosamide, oxyclozanide) to target the gut pathogen. By broth microdilution techniques, we determined the MIC values of the anthelmintics against 16 C. difficile isolates of defined PCR-ribotype. The anthelmintics broadly inhibited C. difficile growth in vitro via a membrane depolarization mechanism. Interestingly, the salicylanilides were bactericidal against logarithmic- and stationary-phase cultures of the BI/NAP1/027 strain 4118. The salicylanilides were poorly active against select gut commensals (Bacteroides, Bifidobacterium and Lactobacillus species), and were non-hemolytic and non-toxic to mammalian cell lines HepG2 and HEK 293T/17 within the range of their in vitro MICs and MBCs. The salicylanilide anthelmintics exhibit desirable properties for repositioning as anti-C. difficile agents.
authors.affiliation: Departments of Chemistry and Immunology and Microbial Science, The Skaggs Institute for Chemical Biology, and The Worm Institute of Research and Medicine (WIRM), The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, United States.
authors.forename: Major
authors.initials: M
authors.lastname: Gooyit
authors.affiliation: Departments of Chemistry and Immunology and Microbial Science, The Skaggs Institute for Chemical Biology, and The Worm Institute of Research and Medicine (WIRM), The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, United States.
authors.forename: Kim D
authors.initials: KD
authors.lastname: Janda
mesh_terms: D000818:Animals; D000871:Anthelmintics / Q000737:chemistry / Q000494:pharmacology*; D000890:Anti-Infective Agents / Q000494:pharmacology; D016360:Clostridioides difficile / Q000187:drug effects* / Q000254:growth & development / Q000302:isolation & purification; D057809:HEK293 Cells; D006461:Hemolysis / Q000187:drug effects; D056945:Hep G2 Cells; D006801:Humans; D007700:Kinetics; D008564:Membrane Potentials / Q000187:drug effects; D008826:Microbial Sensitivity Tests; D012458:Salicylanilides / Q000737:chemistry / Q000494:pharmacology; D012756:Sheep; D013997:Time Factors; D014774:Virulence / Q000187:drug effects
chemical_list: D000871:Anthelmintics; D000890:Anti-Infective Agents; D012458:Salicylanilides; C034596:salicylanilide