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Nanomechanics of Drug-target Interactions and Antibacterial Resistance Detection
Published on: October 25, 2013
Attenuating the Selection of Vancomycin Resistance Among Enterococci through the Development of Peptide-Based
Ryan W Mull1, Alec A Brennan1, Brittany R Russ1
1Department of Chemistry, University of Nevada, Reno, 1664 North Virginia Street, Reno, Nevada 89557, United States.
Abstract:
The emergence and spread of multidrug resistant (MDR) pathogens with acquired resistance to almost all available antimicrobial agents has severely threatened the international healthcare community over the last two decades. The last resort antibiotic vancomycin is critical for treatment of several of these pathogens; howeverc vancomycin resistance is spreading due to the undesired accumulation of IV vancomycin in the colon post-treatment. This accumulation exerts selective pressure upon members of the colonic microflora, including Enterococci, which possess vancomycin resistance genes. To ensure the continual effectiveness of vancomycin in the clinical setting by preventing the spread of antibiotic resistance, it is crucial to develop strategies that reduce selective pressure on the colonic microflora while allowing vancomycin to maintain its desired activity at the site of infection. Herein we report that modification of the native l-Lys-d-Ala-d-Ala vancomycin binding site can be used to produce peptides with the ability to competitively bind vancomycin, reducing its activity against susceptible Enterococci. Moreover, several modifications to the N-termini of the native tripeptide have produced compounds with enhanced vancomycin binding activity, including several analogs that were designed to covalently bind vancomycin, thereby acting as suicide inhibitors. Finally, in a mixed culture of susceptible and resistant bacteria, a single lead compound was found to protect high ratios of susceptible bacteria from vancomycin over the course of a week-long period, preventing the selection for vancomycin-resistant Enterococci. These findings demonstrate the ability of these peptides as potential therapeutic adjuvants for counteracting the undesired accumulation of colonic vancomycin, allowing for protection of the colonic microflora.
Insights
New peptides can bind vancomycin, reducing its impact on gut bacteria. This strategy protects susceptible bacteria from vancomycin resistance, preserving the effectiveness of this crucial antibiotic.
Area of Science:
- Microbiology and Infectious Diseases
- Pharmacology and Drug Development
- Biochemistry and Molecular Biology
Background:
- Multidrug-resistant (MDR) pathogens pose a significant global health threat.
- Vancomycin resistance is increasing due to vancomycin accumulation in the colon, promoting resistance in gut microflora like Enterococci.
- Reducing selective pressure on the colonic microflora is essential for maintaining vancomycin's clinical efficacy.
Purpose of the Study:
- To develop strategies that mitigate vancomycin's undesired accumulation in the colon.
- To create therapeutic adjuvants that protect susceptible gut bacteria from vancomycin's selective pressure.
- To maintain vancomycin's effectiveness against infections while preventing the spread of antibiotic resistance.
Main Methods:
- Modification of the vancomycin binding site (l-Lys-d-Ala-d-Ala) on peptides to create competitive vancomycin binders.
- Design of peptide analogs, including suicide inhibitors, with enhanced vancomycin binding activity.
- Testing lead compounds in mixed bacterial cultures to assess protection of susceptible bacteria over time.
Main Results:
- Modified peptides competitively bind vancomycin, reducing its activity against susceptible Enterococci.
- Several peptide analogs demonstrated enhanced vancomycin binding, with some designed as covalent suicide inhibitors.
- A lead peptide compound protected susceptible bacteria from vancomycin in mixed cultures for a week, preventing resistance selection.
Conclusions:
- Peptide modification of the vancomycin binding site is a viable strategy to counteract colonic vancomycin accumulation.
- These peptides act as potential therapeutic adjuvants, protecting the colonic microflora from vancomycin-induced selective pressure.
- The developed peptides offer a promising approach to preserve the clinical utility of vancomycin and combat antimicrobial resistance.
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