Halogenated and metallic scaffolds as novel efflux pump inhibitors: mechanistic insight in overcoming antimicrobial and cross-domain resistance

Antimicrobial resistance (AMR) is increasing rapidly, necessitating the development of non-traditional therapeutic approaches. Overexpression of bacterial efflux pumps mediates active extrusion of drugs and is a major mechanism underlying multidrug resistance (MDR) in both Gram-negative and Gram-positive pathogens. Inhibition of efflux pumps (EPIs) can restore the activity of conventional antibiotics that have lost efficacy due to resistance. Here, we examine two classes of non-antibiotic adjuvants: halogenated small molecules and metal-based coordination complexes or nanoparticles. Halogen bonding and related chemical modifications can modulate membrane permeability and influence binding kinetics within bacterial transporters. Metal-based antimicrobial compounds utilize specific three-dimensional geometries and iron-mimicry to disrupt microbial transport systems. Notably, although microbial efflux pumps and mammalian multidrug transporters are structurally and mechanistically distinct, they share a functional role in reducing intracellular drug accumulation. This functional convergence provides a rationale for investigating whether selected EPI scaffolds developed in antimicrobial systems may also modulate resistance-associated transport processes in cancer. However, evidence supporting such cross-domain activity remains predominantly preclinical, and functional activity in one biological system should not be interpreted as evidence of therapeutic equivalence or clinical transferability to the other. By integrating structure-activity relationships, transporter mechanisms, microenvironmental pH effects, and translational limitations, this review highlights the potential of halogenated and metal-based scaffolds as experimental EPI platforms while emphasizing the substantial pharmacological, safety, and validation challenges that remain before clinical application.