A Novel Strategy to Combat Antimicrobial Resistance via Molecular Co-Assembly

The Challenge of Antimicrobial Resistance (AMR)

AMR represents one of the most serious global public health threats of the modern era, responsible for at least 1 million deaths annually worldwide—a figure anticipated to increase progressively ^[1]. Scientific research indicates that this crisis stems not only from the spread of resistant bacterial strains but also from complex underlying biological mechanisms: firstly, bacteria can efficiently transfer resistance genes via plasmids, with certain "superplasmids" capable of conferring resistance to multiple first-line and even last-resort antibiotics^[2]; secondly, some pathogens may paradoxically enhance their virulence by discarding specific resistance mechanisms, potentially increasing disease severity and patient mortality^[3]. Compounding this issue, no truly novel class of antibiotics has been introduced into clinical use since the 1990s—a gap exceeding three decades, leading to a significantly depleted antimicrobial arsenal. Consequently, the development of innovative therapeutic strategies to address the current treatment impasse has become an urgent global imperative.

The Application of Nanozymes in Combating AMR

Nanozymes, a class of artificial nanomaterial exhibiting enzyme-mimetic catalytic properties, are increasingly recognized as promising agents in combating AMR and have emerged as a frontier research domain with transformative potential^[5]. These nanozymes can generate reactive oxygen species (ROS) and other antibacterial agents via catalytic reactions, resulting in direct damage to bacterial cell membranes, DNA, and other essential cellular components, thereby enable the effective elimination of various drug-resistant pathogens, such as methicillin-resistant Staphylococcus aureus (MRSA)^[6-7]. More importantly, their multi-mechanistic physicochemical bactericidal mode makes it difficult for bacteria to develop resistance, offering a promising avenue to address the current AMR crisis.

Furthermore, nanozymes exhibit the capacity to penetrate and disrupt robust bacterial biofilms, a characteristic critical for the effective management of chronic and persistent infections. The immobilization of nanozymes on medical dressings has been shown to achieve over 90% elimination of Candida albicans within 10 minutes^[8], indicating their strong antimicrobial efficacy and considerable potential for practical clinical applications. Consequently, nanozymes can be regarded as a powerful tool in confronting the challenges of the "post-antibiotic era"^[7].

Design and Synthesis of a Novel Antibiotic Nanozymes

Herein, we report the design of a novel class of antibiotic nanozymes via molecular co-assembly of antibiotics with hemin chloride, aimed at addressing AMR^[9].

The synthesis of these antibiotic nanozymes exhibits exceptional versatility. A series of representative antibiotics were selected, including gentamicin (GM) and fluconazole (FCZ), along with virtual screening of molecular candidates such as rapamycin (RAPA) and ceftriaxone.Each of these antibiotics effectively co-assembled with hemin chloride through axial coordination and copolymerization, resulting in the formation of stable antibiotic nanozymes.

One of the Antibacterial Mechanisms of Antibiotic Nanozymes

The antibiotic nanozymes exert potent bactericidal effects through the following multifaceted mechanisms^[10]:

1. (1) effective degradation of bacterial biofilms^[11];
2. (2) induction of oxidative damage in bacterial cells via peroxidase (POD)-like activity;
3. (3) promotion of bacterial ferroptosis by functioning as ferroptosis inducers^[12];
4. (4) intracellular release of constituent antibiotics, enabling synergistic antibacterial effects.