Nanotechnology as a Catalyst for Reintroducing Abandoned or Therapeutically Constrained Antimicrobial Agents: Opportunities and Translational Challenges.
Abstract
The global rise in antimicrobial resistance, increasing rates of emerging and re-emerging viral infections, and the persistent burden of fungal and parasitic diseases have intensified the need for alternative anti-infective therapeutic strategies; a challenge further compounded by the diminishing pipeline of novel therapeutic agents. Historically, numerous compounds showed potent broad-spectrum activity against bacterial, viral, fungal, and parasitic pathogens but failed to achieve widespread clinical adoption due to significant limitations, including systemic toxicity, poor selectivity, rapid degradation, unfavorable pharmacokinetics, and off-target host damage. Consequently, many of these promising therapeutic agents were abandoned despite their demonstrated efficacy. Advances in nanotechnology have revitalized interest in these historically neglected compounds by enabling targeted delivery, controlled release, improved biodistribution, and reduced toxicity, offering strategies to improve the therapeutic index of agents once considered clinically impractical. Specifically, this review examines how nanotechnology can reshape the translational potential of therapeutically constrained anti-infective agents and highlights key examples, including halogen-based antimicrobials, metal-derived therapeutics, reactive oxygen and nitrogen species, and membrane-active compounds. We discuss how these technologies address historical barriers to therapeutic application and critically evaluate the remaining barriers hindering clinical translation and long-term biological interactions. Collectively, we propose that the next generation of anti-infective therapeutics may emerge not solely from discovering entirely new compounds, but from strategically reengineering abandoned agents using advanced nanotechnology-enabled delivery systems.
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