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An Enzymatic Antibiotic Adjuvant Modulates the Infectious Microenvironment to Overcome Antimicrobial Resistance of
Min Wei1,2, Jiahe Wu1,3, Heng Sun1
1Institute of Pharmaceutics, Hangzhou Institute of Innovative Medicine, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China.
Abstract:
The emergence and evolution of antimicrobial resistance (AMR) pose a significant challenge to the current arsenal to fight infection. Antibiotic adjuvants represent an appealing tactic for tackling the AMR of pathogens, however, their practical applications are greatly constrained by the harsh infectious microenvironment. Herein, it is found that silver nanoclusters (Ag NCs) can possess tunable enzymatic activities to modulate infectious microenvironments. Based on this finding, an enzymatic nanoadjuvant (EnzNA) self-assembled from Ag NCs, which is inert under neutral physiological conditions but can readily disassemble into isolated Ag NCs exhibiting biofilm destructive oxidase-mimetic activity in the acidic biofilm microenvironment, is developed. Once internalized into the neutral cytoplasm of bacteria, Ag NCs switch to reveal the thiol oxidase-mimetic activity to suppress ribosomal biogenesis for AMR reversal and evolution inhibition of pathogens. Consequently, EnzNAs revitalize various existing antibiotics against methicillin-resistant Staphylococcus aureus, and potentiate the antibiotic efficacy against biofilm-mediated skin infection and lethal lung infection in mice. These findings highlight the capability of enzyme-mimetic nanomaterials to modulate the infectious microenvironment and potentiate antibiotics, providing a paradigm shift for anti-infection therapy.
Insights
This study introduces an enzymatic nanoadjuvant (EnzNA) using silver nanoclusters (Ag NCs) to combat antimicrobial resistance (AMR). EnzNAs effectively reverse AMR and enhance antibiotic efficacy against challenging infections.
Area of Science:
- Biomaterials Science
- Nanotechnology
- Infectious Diseases
Background:
- Antimicrobial resistance (AMR) is a growing global health threat.
- Current antibiotic adjuvants face limitations due to harsh infectious microenvironments.
- Silver nanoclusters (Ag NCs) show potential for modulating these environments.
Purpose of the Study:
- To develop an enzymatic nanoadjuvant (EnzNA) from Ag NCs.
- To engineer EnzNAs that are active in acidic microenvironments and bacterial cytoplasm.
- To investigate EnzNAs' ability to reverse AMR and potentiate antibiotic treatments.
Main Methods:
- Self-assembly of Ag NCs into an EnzNA.
- Evaluation of EnzNA activity in acidic and neutral pH conditions.
- Assessment of EnzNA's effect on bacterial ribosomal biogenesis and AMR reversal.
- In vivo testing of EnzNAs in combination with antibiotics against bacterial infections in mice.
Main Results:
- Developed EnzNA is inert at neutral pH but active in acidic conditions, exhibiting biofilm-destructive oxidase-mimetic activity.
- Internalized Ag NCs display thiol oxidase-mimetic activity, suppressing ribosomal biogenesis and reversing AMR.
- EnzNAs significantly enhanced antibiotic efficacy against methicillin-resistant Staphylococcus aureus.
- Potentiated antibiotic treatment of biofilm-mediated skin and lethal lung infections in mouse models.
Conclusions:
- Enzyme-mimetic nanomaterials can effectively modulate infectious microenvironments.
- EnzNAs offer a novel strategy to overcome AMR and enhance existing antibiotics.
- This approach presents a paradigm shift for developing next-generation anti-infective therapies.
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