title: Evaluating the Effects of Surotomycin Treatment on Clostridium difficile Toxin A and B Production, Immune Response, and Morphological Changes.
abstract: Surotomycin is a cyclic lipopeptide in development for Clostridium difficile-associated diarrhea. This study aimed to assess the impact of surotomycin exposure on C. difficile toxin A and B concentrations and the associated changes in immune response in comparison to vancomycin and metronidazole. Time-kill curve assays were performed using strain R20291 (BI/NAP1/027) at supra-MICs (4× and 40×) and sub-MICs (0.5×) of surotomycin and comparators. Following treatment, CFU counts, toxin A and B concentrations, and cellular morphological changes using scanning electron microscopy were examined. Inflammatory response was determined by measuring interleukin-8 (IL-8) concentrations from polarized Caco-2 cells exposed to antibiotic-treated C. difficile growth media. Supra-MICs (4× and 40×) of surotomycin resulted in a reduction of vegetative cells over 72 h (4-log difference, P < 0.01) compared to controls. These results correlated with decreases of 77% and 68% in toxin A and B production at 48 h, respectively (P < 0.005, each), which resulted in a significant reduction in IL-8 concentration compared to controls. Similar results were observed with comparator antibiotics. Bacterial cell morphology showed that the cell wall was broken apart by surotomycin treatment at supra-MICs while sub-MIC studies showed a "deflated" phenotype plus a rippling effect. These results suggest that surotomycin has potent killing effects on C. difficile that results in reduced toxin production and attenuates the immune response similar to comparator antibiotics. The morphological data also confirm observations that surotomycin is a membrane-active antibiotic.
authors.affiliation: University of Houston College of Pharmacy, Houston, Texas, USA.
authors.forename: Bradley T
authors.initials: BT
authors.lastname: Endres
authors.affiliation: University of Houston College of Pharmacy, Houston, Texas, USA.
authors.forename: Eugénie
authors.initials: E
authors.lastname: Bassères
authors.affiliation: University of Houston College of Pharmacy, Houston, Texas, USA.
authors.forename: Mohammed
authors.initials: M
authors.lastname: Khaleduzzaman
authors.affiliation: University of Houston College of Pharmacy, Houston, Texas, USA.
authors.forename: M Jahangir
authors.initials: MJ
authors.lastname: Alam
authors.affiliation: Merck and Co, Inc., Kenilworth, New Jersey, USA.
authors.forename: Laurent
authors.initials: L
authors.lastname: Chesnel
authors.affiliation: University of Houston College of Pharmacy, Houston, Texas, USA kgarey@central.uh.edu.
authors.forename: Kevin W
authors.identifier: 0000-0003-2063-7503
authors.initials: KW
authors.lastname: Garey
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000096:biosynthesis*; D001427:Bacterial Toxins / Q000096:biosynthesis*; D018938:Caco-2 Cells; D045744:Cell Line, Tumor; D016360:Clostridioides difficile / Q000187:drug effects* / Q000276:immunology* / Q000378:metabolism; D004768:Enterotoxins / Q000096:biosynthesis*; D006801:Humans; D016209:Interleukin-8 / Q000276:immunology; D055666:Lipopeptides / Q000494:pharmacology*; D008795:Metronidazole / Q000494:pharmacology; D008826:Microbial Sensitivity Tests; D008855:Microscopy, Electron, Scanning; D010456:Peptides, Cyclic / Q000494:pharmacology*; D014640:Vancomycin / Q000494:pharmacology
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D001427:Bacterial Toxins; C574454:CB-183,315; C508606:CXCL8 protein, human; D004768:Enterotoxins; D016209:Interleukin-8; D055666:Lipopeptides; D010456:Peptides, Cyclic; C041348:tcdA protein, Clostridium difficile; C031815:toxB protein, Clostridium difficile; D008795:Metronidazole; D014640:Vancomycin