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Updated: Aug 23, 2025
Nanomechanics of Drug-target Interactions and Antibacterial Resistance Detection
Published on: October 25, 2013
Targeting Vancomycin-Resistant Enterococci (VRE) Infections and Van Operon-Mediated Drug Resistance Using Dimeric
Varsha Saini1, Devashish Mehta1, Siddhi Gupta1
1Laboratory of Nanotechnology and Chemical Biology, Regional Centre for Biotechnology, NCR Biotech Science Cluster, 3rd Milestone, Faridabad-Gurgaon Expressway, Faridabad 121001, Haryana, India.
Abstract:
Emergence of vancomycin resistance in Gram-positive bacteria and the prevalence of vancomycin-resistant Enterococci (VRE) infections are highly alarming as very limited antibiotic options are available against VRE infections. Here, we present the synthesis of cholic acid-derived dimeric amphiphiles where two cholic acid moieties are tethered through carboxyl terminals using different alkylene spacers. Our investigations revealed that dimer 5 possessing a propylene spacer and glycine-valine peptides tethered on hydroxyl groups is the most effective antimicrobial against VRE. Dimer 5 can permeabilize bacterial membranes, generate reactive oxygen species, and clear preformed biofilms. We further demonstrate that dimer 5 downregulates vancomycin-mediated transcriptional activation of the vanHAX gene cluster and does not allow VSE to develop vancomycin resistance until 100 generations. Therefore, this study, for the first time, presents a bacterial membrane-targeting amphiphile that can mitigate VRE infections and inhibit the emergence of vancomycin resistance.
Insights
A novel dimeric amphiphile effectively combats vancomycin-resistant Enterococci (VRE) infections by targeting bacterial membranes. This compound also prevents vancomycin-resistant strains from developing further resistance, offering a new strategy against VRE.
Area of Science:
- Medicinal Chemistry
- Antimicrobial Resistance
- Bacterial Pathogenesis
Background:
- Vancomycin-resistant Enterococci (VRE) infections pose a significant global health threat due to limited treatment options.
- The emergence and spread of VRE necessitate the development of novel antimicrobial strategies.
Purpose of the Study:
- To synthesize and evaluate cholic acid-derived dimeric amphiphiles as potential agents against VRE infections.
- To investigate the mechanism of action and resistance-inhibiting properties of the most effective compound.
Main Methods:
- Synthesis of cholic acid-derived dimeric amphiphiles with varying alkylene spacers and peptide modifications.
- Antimicrobial activity testing against VRE strains.
- Assessment of bacterial membrane permeabilization and reactive oxygen species generation.
- Evaluation of biofilm eradication capabilities.
- Analysis of vancomycin resistance gene cluster (vanHAX) downregulation and resistance development in VSE.
Main Results:
- Dimer 5, featuring a propylene spacer and glycine-valine peptides, demonstrated potent antimicrobial activity against VRE.
- Dimer 5 effectively permeabilized bacterial membranes, induced reactive oxygen species, and cleared preformed VRE biofilms.
- Dimer 5 downregulated vancomycin-mediated vanHAX gene activation and prevented vancomycin-susceptible Enterococci (VSE) from developing resistance for up to 100 generations.
Conclusions:
- Cholic acid-derived dimeric amphiphiles represent a promising new class of antimicrobials against VRE.
- Dimer 5 exhibits a multi-pronged mechanism of action, targeting bacterial membranes and inhibiting resistance development.
- This study offers a novel therapeutic approach to mitigate VRE infections and combat antimicrobial resistance.
