Innovative non-antibiotic strategies for treating bacterial infections

Abstract

The battle against bacterial infections underscores the significance of human resilience and scientific ingenuity throughout medical history. Although the discovery of antibiotics in the early 20th century revolutionized the treatment of severe bacterial infections, their efficacy is currently threatened by the alarming rise of antibiotic resistance. This phenomenon, driven by overprescription, misuse of antibiotics, and bacterial adaptability, poses a substantial global health threat that necessitates urgent innovation in antimicrobial strategies. The World Health Organization forecasts that antibiotic-resistant bacteria could cause up to 10 million deaths annually by 2050, underscoring the critical need for alternative therapies beyond traditional antibiotics. This research aims to develop novel non-antibiotic methods for treating bacterial infections. Initially, various exogenous-responsive nanomaterials were designed using sonodynamic therapy (SDT). Leveraging SDT's deep tissue penetration capabilities, ultrasound-responsive nanoparticles ZnTCPP@ZnO were developed, which demonstrated activated oxygen-mediated killing of P. acnes with an antibacterial efficiency of 99.73% under 15 minutes of ultrasound irradiation. These exogenous-responsive materials offer rapid and efficient non-antibiotic antibacterial methods with minimal biotoxicity. In addition to exploring newly designed biomaterials for bacterial infection treatment, we sought to identify and develop effective antibacterial small molecules from natural compounds. Given the complexity of natural extracts and the time-consuming extraction processes, we implemented an artificial intelligence (AI) assisted screening strategy targeting bacterial RNA polymerase (RNAP) and discovered the natural antibacterial small molecule Epirubicin (Epi). Epi binds to specific residues on RNAP, inhibiting its activity and affecting bacterial metabolism, thus effectively achieving bactericidal effects. Beyond developing novel antibacterial agents as antibiotic alternatives, we focused on creating new drug delivery systems (DDS) to optimize the therapeutic efficacy of these agents. A sodium hyaluronate microneedle (MN) patch was designed to mediate the transdermal delivery of these nanoparticles, effectively delivering the antibacterial agents to subcutaneous or deeper infection sites. The stability and efficacy of the antibacterial agents are enhanced by this system. The microneedle system was validated using a subcutaneous infection model of acne, which often fails due to the epidermal barrier and increased resistance, and significant therapeutic outcomes were obtained without the use of antibiotics. In summary, this multifaceted research developed exogenous-responsive antimicrobial nanomaterials and natural antimicrobial small molecules, while designing efficient microneedle delivery systems. Through in vitro experiments and subcutaneous bacterial infection models, this work lays a solid foundation for the future integration of artificial intelligence with materials science, aiming to quickly and effectively address bacterial infections without relying on traditional antibiotics.