Abstract
The ability of vancomycin-arginine (V-r) to extend the spectrum of activity of glycopeptides to Gram-negative bacteria was investigated. Its MIC towards Escherichia coli, including β-lactamase expressing Ambler classes A, B, and D, was 8 to 16 μg/ml. Addition of 8 times the MIC of V-r to E. coli was acutely bactericidal and associated with a low frequency of resistance (<2.32 × 10-10). In vivo, V-r markedly reduced E. coli burden by >7 log10 CFU/g in a thigh muscle model. These data warrant further development of V-r in combatting E. coli, including resistant forms.
Highlights
The ability of vancomycin-arginine (V-r) to extend the spectrum of activity of glycopeptides to Gram-negative bacteria was investigated
Its molecular structure has been successfully manipulated to create a broader spectrum of activity in the targeting of Gram-negative bacteria via adjuvant, formulation, and cationic/lipophilic interventions [10, 11] or synergy with existing Gram-negative antibiotics [12, 13]
The covalent conjugation of L-arginine to vancomycin, to produce vancomycin-L-arginine (V-R), led to promising Gram-negative properties via a cell wall mode of action [14]. These findings encouraged us to further characterize the corresponding diastereomer vancomycin-D-arginine (V-r) in animal models of E. coli infection using the D-isomer of arginine to reduce the risk of conjugate hydrolysis (Fig. 1)
Summary
Rendella aSuperTrans Medical Ltd., Ness Ziona, Israel bMagic Bullet Consulting, London, United Kingdom cDepartment of Pharmacy Practice, Chicago College of Pharmacy and Department of Pharmacology, College of Graduate Studies, Midwestern University, Downers Grove, Illinois, USA dDepartment of Chemistry, Stanford University, Stanford, California, USA eDepartment of Chemical and Systems Biology, Stanford University, Stanford, California, USA
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