A Bifunctional Artificial Antibody for Universal Antimicrobial Therapy

Abstract

ABSTRACT Antimicrobial resistance (AMR) is a global health crisis, and multidrug‐resistant ESKAPE pathogens pose a significant threat to current treatments. Antibody therapy is a promising antibacterial strategy to combat AMR, but the inherent instability and limited functional diversity of biological antibacterial antibodies hinder the development of universal therapies. Here, we report the chemically engineered gold‐based bifunctional antibody biomimetic (AuriFAB), which achieves universal antimicrobial therapy against all multidrug‐resistant ESKAPE pathogens. By utilizing dithiocarbamate ligation, AuriFAB attains exceptional colloidal stability under harsh biological conditions and long‐term storage stability exceeding one year in solution. Chemical epitope screening identifies a disulfiram‐engineered AuriFAB that features a bispecific Fab‐mimicking recognition mechanism, targeting FtsZ in Gram‐positive bacteria and lipopolysaccharide in Gram‐negative bacteria, unlocking picomolar binding affinity and enabling nanogram‐per‐milliliter antibacterial efficacy. AuriFAB demonstrates low toxicity, high selectivity, favorable pharmacokinetics, and in vivo metabolizable clearance. This chemical strategy addresses the stability and functionality limitations of biological antibacterial antibodies and provides a universal solution to combat AMR, demonstrating the therapeutic potential of chemistry‐driven biologic mimics.