An Enzymatic Antibiotic Adjuvant Modulates the Infectious Microenvironment to Overcome Antimicrobial Resistance of Pathogens

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.

Nanotechnology‐driven strategies to enhance the treatment of drug‐resistant bacterial infections

“…Additionally, nanoparticles with phototherapeutic properties may accumulate in the skin and undergo photophysical reaction when exposed to sunlight, potentially leading to skin damage. These safety implications require special consideration in the design of combined therapy strategies (Wei, Wu, et al, 2023;Wei, Yang, et al, 2023). The use of nanodelivery systems in combination therapy strategies has opened up new avenues for research.…”

“…Then, the pH-responsive octadecylamine-p(API-Asp) was prepared by ring-opening polymerization of 1-(3-aminopropyl) imidazole and aminolysis reaction. Finally, the pH-responsive enzyme-mimetic antimicrobial nanoparticles EnzNAs were constructed by self-assembly of silver nanotubes with octadecylamine-p(API-Asp) and a polymeric nonionic surfactant Pluronic F127 by emulsification solvent volatilization method (Wei, Wu, et al, 2023;Wei, Yang, et al, 2023). In the acidic biofilm microenvironment, EnzNAs are broken down into isolated Ag NCs with (111) facets that have oxidase (OXD)-like activity.…”

Recent nanotechnology-based strategies for interfering with the life cycle of bacterial biofilms

“…Inhibiting the EPS has been verified as a robust antibiofilm strategy without the development of resistance. 148,149 Destroying the EPS in a mature biofilm can not only enable bacterial exposure but also promote the penetration and diffusion of antibacterial agents in the biofilm. Some components exhibit an inherent EPS-disrupting effect and rhamnolipid is one of the typical examples.…”

Dynamic Microenvironment-Adaptable Hydrogel with Photothermal Performance and ROS Scavenging for Management of Diabetic Ulcer

“…Diabetic ulcers are among the most serious diabetes-related complications, with high mortality and disability rates . Persistent oxidative stress and inflammation are the primary causes of delayed wound healing in diabetic ulcers. , Moreover, diabetic wounds are susceptible to bacterial invasion − and form a special infectious microenvironment with high levels of reactive oxygen species (ROS), low pH, high temperature, overexpressed enzymes, and proinflammatory factors. − These microenvironmental characteristics prevent wound contraction, prolong inflammatory responses, and impair extracellular matrix proliferation, further aggravating wound healing . Clinically, debridement and antibiotic therapy are the primary treatments for diabetic bacterial infections; however, antibiotics can induce drug resistance .…”