Vancomycin C-Terminus Guanidine Modifications and Further Insights into an Added Mechanism of Action Imparted by a Peripheral Structural Modification
- 14 July 2020
- journal article
- research article
- Published by American Chemical Society (ACS) in ACS Infectious Diseases
- Vol. 6 (8), 2169-2180
- https://doi.org/10.1021/acsinfecdis.0c00258
Abstract
A series of vancomycin C-terminus guanidine modifications are disclosed that improve antimicrobial activity, enhance the durability of antimicrobial action against selection or induction of resistance, and introduce a synergistic mechanism of action independent of D-Ala-D-Ala binding and inhibition of cell wall biosynthesis. The added mechanism of action results in induced bacterial cell permeability, which we show may involve interaction with cell envelope teichoic acid. Significantly, the compounds examined that contain two combined peripheral modifications, a (4-chlorobiphenyl)methyl (CBP) and C-terminus guanidinium modification, offer opportunities for new treatments against not only vancomycin-sensitive, but especially vancomycin-resistant bacteria where they act by two synergistic and now durable mechanisms of action independent of D-Ala-D-Ala/D-Lac binding and display superb antimicrobial potencies (MIC 0.6−0.15 μg/mL, VanA VRE). For the first time, we demonstrate that the synergistic behavior of the peripheral modifications examined requires the presence of both the CBP and guanidine modifications in a single molecule versus their combined use as an equimolar mixture of singly modified compounds. Finally, we show that a prototypical member of the series, G3-CBP-vancomycin (15), exhibits no hemolytic activity, displays no mammalian cell growth inhibition, and possesses improved and especially attractive in vivo pharmacokinetic (PK) properties.Funding Information
- National Cancer Institute (CA041101)
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