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Updated: Oct 24, 2025
Nanomechanics of Drug-target Interactions and Antibacterial Resistance Detection
Published on: October 25, 2013
Vancomyxins: Vancomycin-Polymyxin Nonapeptide Conjugates That Retain Anti-Gram-Positive Activity with Enhanced
Emma van Groesen1, Cornelis J Slingerland1, Paolo Innocenti1
1Biological Chemistry Group, Institute of Biology Leiden, Leiden University, Sylviusweg 72, 2333 BE Leiden, The Netherlands.
Abstract:
Vancomycin functions by binding to lipid II, the penultimate bacterial cell wall building block used by both Gram-positive and Gram-negative species. However, vancomycin is generally only able to exert its antimicrobial effect against Gram-positive strains as it cannot pass the outer membrane (OM) of Gram-negative bacteria. To address this challenge, we here describe efforts to conjugate vancomycin to the OM disrupting polymyxin E nonapeptide (PMEN) to yield the hybrid "vancomyxins". In designing these hybrid antibiotics, different spacers and conjugation sites were explored for connecting vancomycin and PMEN. The vancomyxins show improved activity against Gram-negative strains compared with the activity of vancomycin or vancomycin supplemented with PMEN separately. In addition, the vancomyxins maintain the antimicrobial effect of vancomycin against Gram-positive strains and, in some cases, show enhanced activity against vancomycin-resistant strains. The hybrid antibiotics described here have reduced nephrotoxicity when compared with clinically used polymyxin antibiotics. This study demonstrates that covalent conjugation to an OM disruptor contributes to sensitizing Gram-negative strains to vancomycin while retaining anti-Gram-positive activity.
Insights
Researchers developed novel hybrid antibiotics called vancomyxins by linking vancomycin to polymyxin E nonapeptide (PMEN). These vancomyxins effectively target Gram-negative bacteria by disrupting their outer membrane while retaining activity against Gram-positive strains.
Area of Science:
- Microbiology
- Infectious Diseases
- Drug Discovery
Background:
- Vancomycin is a critical antibiotic for Gram-positive infections but ineffective against Gram-negative bacteria due to their outer membrane.
- Polymyxin antibiotics can disrupt the Gram-negative outer membrane but have significant nephrotoxicity.
- Developing new strategies to overcome antibiotic resistance and expand the spectrum of activity is crucial.
Purpose of the Study:
- To create novel hybrid antibiotics, termed vancomyxins, by conjugating vancomycin with polymyxin E nonapeptide (PMEN).
- To evaluate the efficacy of vancomyxins against Gram-negative bacteria, including vancomycin-resistant strains.
- To assess the safety profile, specifically nephrotoxicity, of the developed vancomyxins.
Main Methods:
- Conjugation of vancomycin to PMEN using various spacers and conjugation sites to create vancomyxin hybrids.
- In vitro testing of vancomyxin activity against Gram-positive and Gram-negative bacterial strains.
- Comparative analysis of vancomyxin efficacy against vancomycin and vancomycin plus PMEN separately.
- Assessment of nephrotoxicity in comparison to clinically used polymyxin antibiotics.
Main Results:
- Vancomyxins demonstrated improved antimicrobial activity against Gram-negative strains compared to vancomycin alone.
- The hybrid antibiotics retained or enhanced activity against Gram-positive strains, including vancomycin-resistant strains.
- Vancomyxins exhibited reduced nephrotoxicity compared to existing polymyxin antibiotics.
Conclusions:
- Covalent conjugation of vancomycin to an outer membrane disruptor (PMEN) effectively sensitizes Gram-negative bacteria to vancomycin.
- Vancomyxins represent a promising new class of antibiotics with broad-spectrum activity and improved safety.
- This approach offers a viable strategy for combating challenging Gram-negative infections and addressing antibiotic resistance.
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