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

Abstract

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.