Glycopeptide antibiotic combination therapy

Inventors

Seyedsayamdost, Mohammad R. • Chioti, Vasiliki T. • Davis, Katherine M. • McWhorter, Kirklin L.

Assignees

University Trustees Of Princeton • Emory University • Princeton University

Abstract

Bacterial infections evading the current antibiotic arsenal warrant new treatment options. The mainstay treatment for Clostridium difficile infections involves administration of the broad-spectrum antibiotic vancomycin, which also depletes the gut microbiome and its natural defenses. This leads to recurrent C. difficile infections in 20-30% of patients. Alternative treatment options are limited, triggering a perpetual cycle of relapse and recovery that may eventually lead to death. Keratinicyclin B represents a glycopeptide antibiotic chemotype with a mechanism of action that is selective for Clostridia. When combined, vancomycin (or other glycopeptide antibiotic) and keratinicyclin B interact synergistically to inhibit the growth of C. difficile at concentrations far lower than their respective minimal inhibitory concentrations. Such a combination therapy could allow for targeted colonization clearance at low antibiotic doses, thereby minimizing toxicity and reducing the likelihood of relapse.

Core Innovation

The invention relates to keratinicyclin B, described as selective for Clostridia, combined with vancomycin, described as a broad-spectrum glycopeptide antibiotic, to synergistically inhibit C. difficile. A primary problem addressed is C. difficile infection recurrence associated with vancomycin, described as being about 20–30%, and the patent focuses on targeted clearance of C. difficile while reducing disruption of the gut microbiota.

The invention provides a pharmaceutical composition and a method in which keratinicyclin B and a second glycopeptide antibiotic consisting of vancomycin are present at synergistic concentrations less than their respective minimal inhibitory concentrations of C. difficile. Checkerboard analysis is described as demonstrating synergy between vancomycin and keratinicyclin B against C. difficile with very low effective titers.

Mechanistic and binding rationale is described for why the combination can be synergistic, including isothermal titration calorimetry showing keratinicyclin B does not bind the D-Ala-D-Ala peptidoglycan terminus, while vancomycin and keratinimicin analogs bind. Crystallography/DFT and modeling are described as indicating steric/stereoelectronic constraints causing loss of binding for keratinicyclin B, supporting differentiated interactions in the combination and specificity that spares other tested gut bacteria associated with colonization resistance.

Claims Coverage

The partial content provides two independent claims. Each independent claim centers on keratinicyclin B paired with vancomycin as glycopeptide antibiotics, used in synergistic concentrations below their respective minimal inhibitory concentrations against C. difficile.

Across the independent claims, the core claim coverage is the use of keratinicyclin B together with a second glycopeptide antibiotic consisting of vancomycin, with both antibiotics present at synergistic concentrations below their respective minimal inhibitory concentrations, either as a pharmaceutical composition or as an administered treatment method that allows synergistic inhibition of C. difficile.

Stated Advantages

Documented Applications