Macrocycle-mediated modulation and repurposing of antibacterial and non-antibacterial drugs.

The rapid emergence of antibiotic resistance has outpaced the discovery of new antibiotics, motivating alternative strategies to enhance existing therapeutics. Supramolecular macrocycles, characterized by defined cavities and host-guest complexation, provide a versatile platform for drug modulation. This review summarizes recent advances in macrocycle-based systems, including cyclodextrins, cucurbiturils, calixarenes, pillararenes, and crown ethers, with emphasis on their ability to modulate both antibacterial and non-antibacterial drugs. Unlike previous reviews focused on new antibacterial materials, this work highlights supramolecular modification and repurposing of existing drugs. Inclusion complexation improves solubility, stability, and controlled release, and can confer antibacterial activity to otherwise inactive molecules. Despite extensive in vitro evidence supporting these effects, translation to and validation in vivo remain limited. Furthermore, physiological factors such as pH, ionic strength, and competing biomolecules can significantly influence host-guest stability and drug release behavior. Collectively, these findings highlight the promise of host-guest systems for antibiotic modulation while underscoring the need for deeper mechanistic understanding and rigorous in vivo evaluation.