Drug Repurposing and Advanced Delivery Systems Targeting Multidrug-Resistant Microorganisms: A Narrative Review

Abstract

Antimicrobial resistance (AMR) is a major global health threat, driven by the spread of multidrug-resistant (MDR) pathogens alongside a declining antibiotic pipeline. Drug repurposing offers a cost-effective, time-efficient alternative by identifying antimicrobial applications for approved drugs with established safety profiles. Agents including auranofin, niclosamide, gallium compounds, phenothiazines, selective serotonin reuptake inhibitors, ticagrelor, and dronedarone show antimicrobial, antibiofilm, antivirulence, and resistance-modifying activity through mechanisms distinct from conventional antibiotics, potentially limiting cross-resistance. However, reported in vitro minimum inhibitory concentrations (MICs) frequently exceed clinical breakpoints and plasma concentrations achievable at approved doses, confining most candidates to adjuvant or local therapy rather than systemic monotherapy. Poor solubility, limited bioavailability, unfavorable pharmacokinetics, and systemic toxicity further constrain clinical translation.

Advanced drug delivery systems (DDS) like nanoparticles, liposomes, metal-organic frameworks, and stimuli-responsive carriers may mitigate these barriers by improving stability, targeting, infection-site accumulation, and controlled release. Such platforms can additionally enhance biofilm penetration, enable intracellular delivery, and permit co-delivery with conventional antibiotics to achieve synergy. Integrating repurposed agents with advanced DDS could therefore address key resistance mechanisms, including biofilm formation, efflux activity, and intracellular persistence, although substantial challenges remain despite encouraging preclinical data.

This review critically evaluates the antimicrobial potential of repurposed non-antimicrobial drugs spanning anti-arthritic, anthelmintic, antineoplastic, psychiatric, and cardiovascular classes, examining mechanisms of action, efficacy evidence, and principal limitations, and assesses how advanced DDS might improve their therapeutic performance against MDR infections. It further identifies major evidence gaps and research priorities to guide development of clinically viable anti-AMR strategies.