A Vancomycin Derivative with a Pyrophosphate‐Binding Group: A Strategy to Combat Vancomycin‐Resistant Bacteria

Abstract

Vancomycin, the drug of last resort for Gram-positive bacterial infections, has also been rendered ineffective by the emergence of resistance in such bacteria. To combat the threat of vancomycin-resistant bacteria (VRB), we report the development of a dipicolyl-vancomycin conjugate (Dipi-van), which leads to enhanced inhibition of cell-wall biosynthesis in VRB and displays in vitro activity that is more than two orders of magnitude higher than that of vancomycin. Conjugation of the dipicolyl moiety, which is a zinc-binding ligand, endowed the parent drug with the ability to bind to pyrophosphate groups of cell-wall lipids while maintaining the inherent binding affinity for pentapeptide termini of cell-wall precursors. Furthermore, no detectable resistance was observed after several serial passages, and the compound reduced the bacterial burden by a factor of 5 logs at 12 mg kg(-1) in a murine model of VRB kidney infection. The findings presented in this report stress the potential of our strategy to combat VRB infections.

Sulfonium, an Underestimated Moiety for Structural Modification, Alters the Antibacterial Profile of Vancomycin Against Multidrug‐Resistant Bacteria

“…[3][4][5] However,a fter over 50years of clinical use,vancomycin-resistant bacteria, including vancomycin-resistant S. aureus (VRSA) and Enterococci (VRE), have emerged and become new challenges in antibacterial treatment. [6] To tackle antibiotic resistance, various modification strategies have been applied to develop novel vancomycin derivatives,such as lipophilic modification on vancosamine, [7] ligand-binding enhancement, [8] attachment of membrane-disrupting fragments, [8c, 9] pyrophosphate-targeting designs, [10] and the modification of the vancomycincore structure by total synthesis. [9e, 11] Recently,acombined modification of lipophilic and cationic motifs on vancomycin has been used to enhance the ability of vancomycin to permeabilize the bacterial membrane,i ncluding vancomycin derivatives carrying C-terminal lipophilic quaternary ammonium moieties from the Halder group [9d] and carrying lysinerich lipopeptides from the Cooper group.…”

Antiplasmodial activity of targeted zinc(II)-dipicolylamine complexes

“…A ZnDPA-vancomycin derivative was recently used to treat antibiotic-resistant bacteria infections in mice without the development of chemoresistance. [33] In addition, ZnDPA-camptothecin conjugates have been reported to selectively target PS-exposing tumors in mice. [34]…”

Developments in Glycopeptide Antibiotics

“…152 As discussed earlier, a zinc-binding dipicolyl moiety was attached to the C -terminus of vancomycin in 8 , to bind to the pyrophosphates of cell-wall lipids. 93 Similarly, a silver-complexing pyridinyl ligand has also been ligated ( 31 ), for use in combination with surface-attached pyridinyl groups to create a vancomycin-silver surface coating that had antimicrobial activity. 153 The C -terminus of vancomycin has also been functionalized with a bone-targeting methoxyphenylamide moiety that binds strongly to hydroxyapatite, attached via a PEG linker, to develop a more effective therapeutic for bone infections.…”