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Re-sensitization of mcr carrying multidrug resistant bacteria to colistin by silver
Qi Zhang1, Runming Wang1, Minji Wang2
1Department of Chemistry, State Key Laboratory of Synthetic Chemistry, and CAS-HKU Joint Laboratory of Metallomics on Health and Environment, The University of Hong Kong, Hong Kong SAR, 999077, People's Republic of China.
Abstract:
Colistin is considered the last-line antimicrobial for the treatment of multidrug-resistant gram-negative bacterial infections. The emergence and spread of superbugs carrying the mobile colistin resistance gene (mcr) have become the most serious and urgent threat to healthcare. Here, we discover that silver (Ag+), including silver nanoparticles, could restore colistin efficacy against mcr-positive bacteria. We show that Ag+ inhibits the activity of the MCR-1 enzyme via substitution of Zn2+ in the active site. Unexpectedly, a tetra-silver center was found in the active-site pocket of MCR-1 as revealed by the X-ray structure of the Ag-bound MCR-1, resulting in the prevention of substrate binding. Moreover, Ag+effectively slows down the development of higher-level resistance and reduces mutation frequency. Importantly, the combined use of Ag+ at a low concentration with colistin could relieve dermonecrotic lesions and reduce the bacterial load of mice infected with mcr-1–carrying pathogens. This study depicts a mechanism of Ag+ inhibition of MCR enzymes and demonstrates the potentials of Ag+ as broad-spectrum inhibitors for the treatment of mcr-positive bacterial infection in combination with colistin.
Insights
Silver ions (Ag+) can restore colistin effectiveness against dangerous superbugs by inhibiting the MCR-1 enzyme. This combination therapy shows promise for treating multidrug-resistant bacterial infections.
Area of Science:
- Antimicrobial resistance research
- Biochemistry and structural biology
- Infectious disease therapeutics
Background:
- Colistin is a critical last-line antibiotic for multidrug-resistant Gram-negative infections.
- The spread of mobile colistin resistance (mcr) genes poses a significant global health threat.
- Novel strategies are urgently needed to overcome colistin resistance.
Purpose of the Study:
- To investigate the potential of silver ions (Ag+) to restore colistin efficacy against mcr-positive bacteria.
- To elucidate the mechanism by which Ag+ inhibits MCR enzymes.
- To evaluate the therapeutic potential of combining Ag+ with colistin.
Main Methods:
- Biochemical assays to determine MCR-1 enzyme inhibition by Ag+.
- X-ray crystallography to reveal the structural basis of Ag+ binding to MCR-1.
- In vitro studies on resistance development and mutation frequency.
- In vivo mouse infection models to assess therapeutic efficacy.
Main Results:
- Ag+ inhibits MCR-1 activity by substituting for Zn2+ in the active site, forming a tetra-silver center.
- Structural analysis revealed Ag+ binding prevents substrate interaction.
- Ag+ reduced the development of high-level resistance and lowered mutation rates.
- Combined low-dose Ag+ and colistin treatment reduced bacterial load and lesions in infected mice.
Conclusions:
- Silver ions effectively inhibit MCR enzymes, restoring colistin's antimicrobial activity.
- Ag+ demonstrates potential as a broad-spectrum inhibitor for treating mcr-positive bacterial infections.
- Combination therapy with Ag+ and colistin offers a promising approach to combatting colistin-resistant superbugs.
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