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: Bradley T Endres, Eugénie Bassères, Mohammed Khaleduzzaman, M Jahangir Alam, Laurent Chesnel, Kevin W Garey
• Journal: Antimicrobial agents and chemotherapy (Antimicrob Agents Chemother) Vol. 60 Issue 6 Pg. 3519-23 (06 2016) ISSN: 1098-6596 [Electronic] United States
• PMID: 27021314 (Publication Type: Comparative Study, Journal Article)
• Copyright: Copyright © 2016, American Society for Microbiology. All Rights Reserved.

Chemical References

• Anti-Bacterial Agents
• Bacterial Proteins
• Bacterial Toxins
• CB-183,315
• CXCL8 protein, human
• Enterotoxins
• Interleukin-8
• Lipopeptides
• Peptides, Cyclic
• tcdA protein, Clostridium difficile
• toxB protein, Clostridium difficile
• Metronidazole
• Vancomycin

Topics

• Anti-Bacterial Agents (pharmacology)
• Bacterial Proteins (biosynthesis)
• Bacterial Toxins (biosynthesis)
• Caco-2 Cells
• Cell Line, Tumor
• Clostridioides difficile (drug effects, immunology, metabolism)
• Enterotoxins (biosynthesis)
• Humans
• Interleukin-8 (immunology)
• Lipopeptides (pharmacology)
• Metronidazole (pharmacology)
• Microbial Sensitivity Tests
• Microscopy, Electron, Scanning
• Peptides, Cyclic (pharmacology)
• Vancomycin (pharmacology)