Vancomycin resistance is currently a major healthcare problem. The development of a catalytic monoclonal antibody (mAb) that hydrolyzes the D-Ala-D-Lac depsipeptide provides a potentially novel antibiotic strategy. A phosphonate hapten design was used to program antibody catalysis. The characteristics of the hapten were shown to be important for obtaining a viable immune response and several catalytic mAbs that cleave a peptidoglycan model substrate. The best mAb afforded a >500-fold rate enhancement over background.
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Shapeshifting bullvalene-linked vancomycin dimers as effective antibiotics against multidrug-resistant gram-positive bacteria.
Proc Natl Acad Sci U S A
April 2023
Cancer Center, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724.
The alarming rise in superbugs that are resistant to drugs of last resort, including vancomycin-resistant enterococci and staphylococci, has become a significant global health hazard. Here, we report the click chemistry synthesis of an unprecedented class of shapeshifting vancomycin dimers (SVDs) that display potent activity against bacteria that are resistant to the parent drug, including the ESKAPE pathogens, vancomycin-resistant (VRE), methicillin-resistant (MRSA), as well as vancomycin-resistant (VRSA). The shapeshifting modality of the dimers is powered by a triazole-linked bullvalene core, exploiting the dynamic covalent rearrangements of the fluxional carbon cage and creating ligands with the capacity to inhibit bacterial cell wall biosynthesis.
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ACS Omega
January 2021
Department of Chemistry and Biochemistry, Baylor University, Waco, Texas 76798, United States.
Vancomycin is a glycopeptide antibiotic produced by used to treat serious infections by Gram-positive pathogens including methicillin-resistant . Vancomycin inhibits cell wall biosynthesis by targeting lipid II, which is the membrane-bound peptidoglycan precursor. The heptapeptide aglycon structure of vancomycin binds to the d-Ala-d-Ala of the pentapeptide stem structure in lipid II.
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January 2017
Department of Chemistry and Biochemistry, Baylor University, Waco, Texas 76798, United States.
Induction of vancomycin resistance in vancomycin-resistant enterococci (VRE) involves replacement of the d-Ala-d-Ala terminus of peptidoglycan (PG) stems with d-Ala-d-Lac, dramatically reducing the binding affinity of vancomycin for lipid II. Effects from vancomycin resistance induction in Enterococcus faecalis (ATCC 51299) were characterized using a combined solid-state nuclear magnetic resonance (NMR) and liquid chromatography-mass spectrometry (LC-MS) analysis. Solid-state NMR directly measured the total amounts of d-Lac and l,d-Ala metabolized from [2-C]pyruvate, accumulated Park's nucleotide, and changes to the PG bridge-linking density during the early exponential growth phase (OD = 0.
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June 2014
Departamento de Química Orgánica y Farmacéutica, Universidad Complutense de Madrid, Pz/Ramón y Cajal s/n. 28040 Madrid (Spain).
Glycopeptide antibiotics, such as vancomycin and teicoplanin, are used to treat life-threatening infections caused by multidrug-resistant Gram-positive pathogens. They inhibit bacterial cell wall biosynthesis by binding to the D-Ala-D-Ala C-terminus of peptidoglycan precursors. Vancomycin-resistant bacteria replace the dipeptide with the D-Ala-D-Lac depsipeptide, thus reducing the binding affinity of the antibiotics with their molecular targets.
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January 2010
Pharmacologie cellulaire et moléculaire, UCL7370 avenue Mounier 73, 1200 Brussels, Belgium.
DD-ligases catalyze the synthesis of the D-Ala-D-Ala and D-Ala-D-Ser dipeptides or the D Ala-D-Lac depsipeptide in an early step of peptidoglycan synthesis. Their function is essential for bacterial growth and specific to bacteria, making them attractive targets for the development of novel antibiotics. This review examines the biochemical and structural features of these enzymes and presents the main families of inhibitors described so far.
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