Glycopeptide Antibiotic Combination Therapy Against Clostridial Infections, In Particular, C. difficile
Princeton Docket # 21-3813
Researchers in the Department of Chemistry, Princeton University, and the Department of Chemistry, Emory University, have identified that when combined, vancomycin and keratinicyclin B interact synergistically to inhibit the growth of C. difficile at concentrations up to 8-fold lower than their respective minimal inhibitory concentrations.
Keratinicyclin B represents a new glycopeptide antibiotic chemotype with a novel mechanism of action that is selective for Clostridia. Experimental results have found that vancomycin and keratinicyclin B exhibit synergistic effects against Clostridium difficile. When administered together, they fully inhibit the growth of C. difficile at concentrations 1/8 their respective minimal inhibitory concentrations. Nanomolar concentrations of vancomycin (~170 nM) and keratinicyclin B (~290 nM) are sufficient to inhibit the growth of >95% of cells in culture. By contrast, the concentration of vancomycin administered is >100 μM (typically 15–20 mg/kg for adults).
Besides Clostridium difficile infection, the combination therapy disclosed herein could find therapeutic utility in other clostridial infections, including clostridial necrotizing enteritis and Clostridium perfringens.
Other glycopeptide antibiotics, such as teicoplanin, also exhibit synergistic interaction with keratinicyclin B. Therefore, combinations of teicoplanin and keratinicyclin B (and other keratinicyclin variants) also provide a useful combination therapy.
Stage of Development
Vancomycin and keratinicyclin B are secondary metabolites produced by soil-dwelling Amycolatopsis strains. Vancomycin is produced on an industrial scale by fermentation and is commercially available. The process for acquiring keratinicyclins in general, and specifically keratinicyclin B, involves fermentation in the presence of small-molecule elicitors and has been described in Nat. Chem. Biol. 2019, 15, 161–168. It has been shown that when combined, vancomycin and keratinicyclin B interact synergistically to inhibit the growth of C. difficile at concentrations 8-fold lower than their respective minimal inhibitory concentrations.
Chioti, V. T.; McWhorter, K. L.; Xu, F.; Jeffrey, P. D.; Davis, K. M.; Seyedsayamdost, M. R. Structural and Functional Analysis of Keratinicyclin Reveals Synergistic Antibiosis with Vancomycin Against Clostridium difficile. ChemRxiv 2021, DOI: 10.26434/chemrxiv.14668545.v1.
Patent protection is pending.
Princeton is currently seeking commercial partners for the further development and commercialization of this opportunity.
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